![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 26, Issue 1, 73-77, January 1998
Department of Pharmacology, The University of Iowa
 |
Abstract |
|---|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
UGT2B7 has been cloned and expressed previously in COS cells and HK293 cells. Two forms have been identified: one with a tyrosine and one with a histidine at position 268. UGT2B7 has been shown to catalyze NSAIDs, catechol estrogens, and morphine-3- and -6-glucuronidation. cDNAs for UGT2B7Y268 and H268 were cloned and stably expressed in HK 293 cells. Studies were designed to test each form for reactivity toward a number of opioid compounds, xenobiotics such as menthol, oxazepam, and propranolol, and androgens such as androsterone and testosterone using membrane preparations derived from HK 293 cells. Both UGT2B7Y and UGT2B7H are highly reactive with many opioids, menthol, androsterone, and (R)- and (S)-propranolol, and similar kinetic values were observed. UGT2B7Y and UGT2B7H react poorly with oxazepam and no difference in (R)- or (S)-glucuronidation rate ratios was found. Thus, UGT2B7Y and H cannot account for the variability in the plasma or urine concentrations of these glucuronides in human populations. Our data suggest that UGT2B7 is a major isoform responsible for the glucuronidation of androsterone. Neither UGT2B7Y nor H catalyzes the glucuronidation of testosterone although each catalyzes the glucuronidation of epitestosterone. UGT2B7 seems to be a major human isoform responsible for the glucuronidation of opioids of the morphinan and oripavine class and is capable of catalyzing the glucuronidation of both the 3- and 6-hydroxyl moieties on these molecules. Thus, UGT2B7 plays a major role in the conversion of morphine to morphine-6-glucuronide, the potent analgesic metabolite of morphine.
| |
Introduction |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
The metabolic
process of glucuronide formation is known to be extremely important for
the conversion of xenobiotics and endobiotics to hydrophilic
metabolites. These glucuronides are excreted rapidly by the liver and
kidney. UDP-glucuronosyltransferases (UGTs,1 EC 2.4.1.17)
catalyze this process. UGTs are intrinsic membrane proteins of the
endoplasmic reticulum and nuclear envelope and are encoded by multiple
genes of at least two families (Mackenzie et al., 1997
).
Members of the UGT1 gene complex share common second through
fifth exons with at least twelve separate exons encoding for specific
proteins with unique N-terminal domains (Ritter et al., 1992). Gene products of the UGT2 family are
transcribed from unique genes. At this time, over 40 individual UGT
isoforms have been identified either by cloning and expression or by
purification procedures from hepatic microsomes (Mackenzie et
al., 1997). Among the UGTs identified for humans, UGT2B7 is a very
important isoform.
In a previous report (Coffman et al., 1997) we showed that
stably expressed human UGT2B7 catalyzed the glucuronidation of opioids
such as morphine and buprenorphine with high efficiency. Morphine is
the most important and widely used opioid analgesic in clinical
medicine and its metabolism must be understood, given the influence of
its rate of metabolism and the recent appreciation of the potential
role of the several metabolites formed in the overall pharmacology of
this agent (Christrup, 1997). Clinical studies have shown that
morphine- 6-O-glucuronide is 2-3 times more effective as an
analgesic than the parent compound, and it has been found to bind with
high affinity to opioid receptors (Osborne et al., 1990). In
contrast, morphine- 3-O-glucuronide does not bind to the
opioid receptors and is devoid of analgesic effects (Oguri et
al., 1987, Pasternak et al., 1987). However, morphine-3-O-glucuronide has been shown to counteract the
analgesic activity of morphine and morphine-6-O-glucuronide
(Smith et al., 1990).
Morphine is a phenanthrene alkaloid with a phenolic 3-hydroxyl group
and an alcoholic 6-hydroxyl moiety. UGT2B7 promotes the glucuronidation
of both hydroxyls with an efficiency ratio quite similar to the ratio
of glucuronides found in human urine, i.e. 7 to 1; 3-OH to
6-OH (Coffman et al., 1997). In addition, codeine, the
3-methoxy derivative of morphine, is efficiently converted to the
6-O-glucuronide by UGT2B7 (Coffman et al., 1997).
Codeine-6-O-glucuronide has been found to produce analgesic
responses in rats and has been shown to produce less immunosuppression
than codeine (Srinivasan et al., 1996). Thus UGT2B7
reactivity with these opioids leads to the production of very important
and clinically relevant metabolites.
UGT2B7 has been cloned and expressed previously with a tyrosine or a
histidine at amino acid 268 (Jin et al., 1993, Ritter et al., 1989). Indeed, questions concerning the substrate
specificity or even the relative reactivity with certain substrates
have been raised. UGT2B7Y was reported to be active toward menthol and
androsterone glucuronide formation by one laboratory (Jin et
al., 1993), while another laboratory has reported that UGT2B7H is
inactive with these substrates (Ritter et al., 1989). More
recently Patel et al. (1995a) have raised a pharmacogenetic
issue for UGT2B7. They proposed that either UGT2B7Y or UGT2B7H accounts
for the variability among the human population in the ratio of oxazepam
(S)- to (R)-glucuronides in urine and plasma
formed from (R, S)-oxazepam. In 10% of human liver microsomal preparations the Km
values of oxazepam were abnormally high for the formation of the
(S)-glucuronide but remained the same for the
(R)-glucuronide formation. They suggest that amino acid 268, either tyrosine or histidine of UGT2B7, accounts for variability of the
(S)-oxazepam glucuronide/(R)-oxazepam glucuronide ratio.
The current study addresses the important role of human UGT2B7 in the catalysis of glucuronidation of opioid compounds, agonists, partial agonists, and opioid antagonists, using stably expressed UGT2B7Y and H and optimized experimental conditions. This work shows also the role of UGT2B7 in the glucuronidation of certain androgenic steroids and the xenobiotics, menthol, propranolol, and oxazepam. UGT2B7 is not an important factor in oxazepam metabolism in humans based on its minimal activity toward this substrate, and differences were not found between the reactivities with oxazepam for the two UGT2B7 isoforms.
| |
Materials and Methods |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
Chemicals.
UDP-[U-14C]GlcUA (319 mCi/mmol) was purchased
from ICN Pharmaceuticals, Inc. (Irvine, CA). Morphine sulfate was
acquired from Merck and Co., Inc. (Rahway, NJ). Diprenorphine,
morphine-3-glucuronide, morphine-6-glucuronide, naloxone, and
naltrexone were acquired from Research Biochemicals Inc. (Natick, MA).
R- and S-propranolol and (+) and (-) menthol were
obtained from Aldrich Chemical Co., (Milwaukee, WI). All other
aglycones, L-
-phosphatidylcholine (type XVI-E from egg yolk),
dithiothreitol, UDP-GlcUA, and horseradish peroxidase-conjugated rabbit
anti sheep IgG were purchased from Sigma Chemical Co. (St. Louis, MO).
Protein assay reagents were from Bio-Rad (Richmond, CA). Western blot
reagents, SuperBlock and SuperSignal substrate, were from Pierce
(Rockford, IL).
Stable Expression of Human UGT2B7Y and UGT2B7H.
The isolation and stable expression of a cDNA coding for human UGT2B7Y
has been described previously by Coffman et al. (1997). The
cDNA coding for UGT2B7H was obtained from the cDNA coding for UGT2B7Y
inserted in Bluescript by exchanging a 5-deoxythymidylic acid for a
5-deoxycytidylic acid using a QuickChange Site-Directed Mutagenesis kit
(Stratagene, LaJolla, CA). The base change resulted in a coding for a
histidine at position 268 instead of a tyrosine. The UGT2B7H DNA was
inserted into the vector DNA3.1 (Invitrogene, Carlsbad, CA) and
expressed in HK293 cells as previously described (Coffman et
al., 1997). Sequence analysis carried out by the DNA facility of
the University of Iowa confirmed the mutation. Membrane preparations
from HK293 cells that stably expressed human UGT2B7Y or UGT2B7H were
prepared according to the method described by King et al.
(1997).
Western Blot Analysis.
Western blots of total protein from membrane preparations were blocked
with SuperBlock according to the manufacturer's instructions. The
primary antibody was a sheep anti-rabbit p-nitrophenol IgG as described by Green et al. (1988). The secondary antibody
was horseradish peroxidase-conjugated rabbit anti-sheep IgG. After incubation with the chemiluminescent substrate, SuperSubstrate, the
blot was analyzed by luminography.
Glucuronidation Assays.
Glucuronidation activity towards opioids in membrane preparations was
assayed using the method described by Puig and Tephly (1986). The
glucuronides of morphine-3 hydroxyl and morphine-6-hydroxyl were
identified and quantified using an HPLC method as described by Coffman
et al. (1997). Analysis of glucuronidation of non-opioids were carried out and analyzed by TLC as described by Green et al. (1994), or in the case of androsterone, testosterone, and epitestosterone by the method of Matern et al. (1994). The
glucuronidation of oxazepam was analyzed using the HPLC method of Vree
et al. (1991) and 14C UDP-GlcUA. The
radioactivity eluted with glucuronide standards was measured. In each
case, optimal pH values and linear product formation were determined
and employed for analysis of rates and kinetics. The concentration of
UDP-GlcUA in the assays was 2 mM. The Km
for UDP-GlcUA was determined using 1mM naloxone.
| |
Results |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
Expression of UGT2B7Y and UGT2B7H
Western blot analysis was carried out on membranes derived from HK293 cells stably expressing UGT2B7Y or H. Results in fig. 1 show the 52 Kd bands of the two UGT2B7 isoforms in varying concentrations.
|
Reactivity of UGT2B7Y and UGT2B7H with Opioids
Table 1 shows results obtained when
membranes containing stably expressed UGT2B7Y or H were studied for
activity toward 18 different opioid derivatives. As demonstrated in a
previous study (Coffman et al., 1997), morphine
glucuronidation rates were high and both 3- and 6-hydroxyl glucuronides
were formed. No differences in rates were found between UGT2B7Y and
UGT2B7H. Naloxone and nalorphine were glucuronidated with as high rates
as morphine, whereas the oripavine derivatives were glucuronidated at
rates nearly 10-fold lower. Studies on various other substituted
morphinans are shown. The only difference between UGT2B7Y and H was
that normorphine and naltriben seem not to be glucuronidated by
UGT2B7H.
|
Kinetics of UGT2B7Y and UGT2B7H with Opioid Substrates
The results of kinetic studies are shown in table 2. Both UGT2B7 isoforms seem to have similar efficiencies for morphinan substrates, among them morphine, codeine, naloxone, nalorphine, and naltrexone. However, buprenorphine had a 10-fold higher efficiency with UGT2B7Y than for the H form. The Km for UDP-GlcUA was similar for both UGT2B7 isoforms, as were efficiency values, using naloxone as aglycone.
|
Reactivity of UGT2B7Y and UGT2B7H with Oxazepam, Androgens, and Menthol
Previous studies from other laboratories have reported data that
were inconsistent with respect to the reactivities of UGT2B7Y or H with
menthol and androsterone (Jin et al., 1993, Ritter et al., 1989). Table 3 shows that
UGT2B7Y or H react equally well with (+) or (-) menthol. Furthermore,
androsterone and epitestosterone are very good substrates for both
isoforms of UGT2B7. Interestingly, testosterone does not react with
either isoform under the conditions employed in these experiments.
Oxazepam is a poor substrate for either isoform of UGT2B7 and the ratio
of (R) to (S) glucuronide is equivalent.
|
Kinetic studies of UGT2B7Y and UGT2B7H with Propranolol and Androsterone
Since oxazepam is a poor substrate with UGT2B7, another important stereoisomeric drug, propranolol, was studied. For this compound, it was possible to obtain the pure (R)- and (S)- forms. Table 4 shows that both UGT2B7Y and H react with high efficiency toward (R)- and (S)-propranolol. Also, no differences in Km values and efficiencies with androsterone were observed for UGT2B7Y and H.
|
| |
Discussion |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
It is clear that UGT2B7 is a UGT isoenzyme of major importance for
the glucuronidation in humans of a large number of clinically important
opioid compounds. This UGT catalyzes glucuronidation of both the 3- and
6-hydroxyl position of morphinan derivatives, such as morphine, and is
also a catalyst of codeine 6-O-glucuronide formation. No
other UGT isoform has been shown to catalyze 6-O glucuronidation, although rat and human UGT1A1 do catalyze the 3-O-glucuronidation of the opioid compounds such as
morphinan derivatives, naltrexone, naloxone, and morphine, and the
oripavine antagonist/partial agonist, buprenorphine (Coffman et
al., 1995, King et al., 1996). UGT2B7H was first cloned
and expressed transiently in COS-1 cells by Ritter et al.
(1989), who found 3,4-catechol estrogens and estriol to be good
substrates but reported that there was no detectable conversion of
morphine to a glucuronide. Jin et al. (1989) reported on the
cloning and transient expression of UGT2B7Y but this isoform, as
expressed in COS-7 cells, was reported to possess no reactivity with
morphine. Technique differences between those studies and the one
reported here may be the reason that morphine glucuronidation was not
detected previously. With respect to opioids, both UGT2B7Y and H, as
stably expressed in HK293 cells, have similar reactivity with the
opioids studied here. Only a few substrates were glucuronidated with
some differences by the two forms of UGT2B7: normorphine,
norbuprenorphine, naltriben, and buprenorphine. The efficiency of
glucuronidation of buprenorphine was 10 times higher for the Y form.
Normorphine and norbuprenorphine seem to possess some different
reactivities because these compounds are less active as substrates for
the H form than the Y form of the enzyme. Both forms catalyze
glucuronidation of morphine and codeine at the 6-OH position, in
contrast to rat UGT2B1, the major catalyst of opioid glucuronidation in
rats, which catalyzes only 3-O-glucuronidation of opioids
(King et al., 1997). For both morphinan and oripavine
structures (fig. 2), it can be concluded
that aliphatic substitutions at the 17-nitrogen position increase the
glucuronidation rate, and that carbon chains allowed for increased
efficiency more than the substitution of an alicyclic group, as was
found for rat UGT2B1 (King et al., 1997). Other structural
differences seem also to play a role for both forms. Hydration of the 7 and 8 positions decreases the catalytic rate 7-fold
(morphine/dihydromorphine), and lack of a substituent at the 6-position
(levorphanol) yields even lower rates. Also, a propene group at
position 6 gives a lower rate than an oxygen substitution
(nalmefene/naltrexone). Substitutions at the 14-position are likewise
important, a hydroxy group increases rates (oxymorphone/hydromorphone).
|
The same trends are seen in the kinetic data for selected compounds.
Naloxone, naltrexone, and hydromorphone are identical compounds except
for the N-substitutions. Lower
Km values for the proteins are favored by
the aliphatic chain substitution over the cyclic, and
Km values are higher where methyl group
substitution is present. The presence of a 14-hydroxy group yields
values of higher Km, and increases the
Vmax (oxymorphone/hydromorphone). The
methoxy substitution on position 3 seems to influence the efficiency of
glucuronidation of the 6-OH position. The efficiency of codeine
glucuronidation was one tenth of that of morphine. Codeine has been
reported (Yue et al., 1989) to be glucuronidated at a lower
rate in the Chinese population when compared with the Caucasian
population, but based on our data no differences in codeine
glucuronidation between UGT2B7Y and UGT2B7H were seen. The observation
of population differences is not likely to be explained by this
polymorphism of UGT2B7.
Patel et al. (1995a) have proposed that the two forms of
UGT2B7, H and Y, account for differences in two human populations with
respect to the apparent differences in the ratio of (R)- and
(S)-oxazepam glucuronides excreted in the urine when a
racemic mixture of oxazepam was administered orally. We did not observe any differences for glucuronidation by UGT2B7Y and H. Activities were
so low for oxazepam that kinetic values could not be obtained accurately. The low rate of reactivity of UGT2B7Y in oxazepam glucuronidation has also been shown by Jin et al. (1993). We
believe, based on this data, that UGT2B7 is not an important isoform
for glucuronidation of oxazepam. The proponents of the role of UGT2B7 in oxazepam metabolism did not show inhibition of oxazepam
glucuronidation by morphine in human liver microsomes (Patel et
al., 1995b), although oxazepam glucuronidation was inhibited by
various NSAIDs. Because oxazepam was found to be a poor substrate with
UGT2B7, the glucuronidations of (R)- and
(S)-propanolol were investigated. Propanolol is a clinically
important adrenergic 
-receptor antagonist and is an excellent
substrate with UGT2B7 isoforms. Neither isoform showed stereoselective
glucuronidation of (R)- or (S)-propanolol, and there were no differences in Km values
with (R)- and (S)-propanolol.
Other laboratories have reported on the glucuronidation of catechol
estrogens and NSAIDs by UGT2B7Y or H (Jin et al., 1993, Ritter et al., 1989) but have disagreed on the reactivity of
these UGT isoforms toward a few substrates such as menthol and
androsterone. The glucuronidations of (+) and (
) menthol were
catalyzed by both enzyme forms, and the kinetics for androsterone
showed no differences between the isoforms. However, the efficiency of
androsterone glucuronidation was found to be so high as to suggest that
UGT2B7 is the major isoform catalyzing 3-hydroxy steroids. This has also recently been reported by Jin et al. (1997). Both
isoforms showed activity towards epitestosterone (17 -ol), but not
towards testosterone (17 -ol).
Human UGT2B7 catalyzes the glucuronidation of a wide variety of
substrates, such as catechol estrogens, androgens, opioids, NSAIDs, and
propanolol. No differences were seen in the present study with either
isoform for most of the compounds tested. The glucuronidation of
morphine and codeine is of special interest. Morphine-6-O-glucuronide is known to be a much more potent
analgesic than its parent compound in humans (Christrup, 1997, Osborne
et al., 1990), and codeine-6-O-glucuronide has
also been found to demonstrate high analgesic potency in rats
(Srinivasan et al., 1996).
Morphine-3-O-glucuronide, the major metabolite of morphine, has no analgesic effect, but has been shown to cause hyperglycemic and
neuroendrocrine potentiating effects in rats (Hashiguchi et al., 1995). In addition, morphine-3-O-glucuronide
antagonizes the respiratory depression induced by morphine and
morphine-6-O-glucuronide (Christrup, 1997, Smith et
al., 1990), which might explain why chronic users of morphine
become tolerant to otherwise lethal doses of morphine. Since UGT2B7
catalyzes the glucuronidation of both morphine and codeine, the two
most widely used analgesic agents of intense pain in humans, our
understanding of the reactivities of this isoenzyme becomes most
important in understanding the regulation of the metabolic pathway of
opioid disposition.
| |
Acknowledgment |
|---|
We wish to thank Mitchell D. Green for helpful discussions in the preparation of this manuscript.
| |
Footnotes |
|---|
Received July 31, 1997; accepted October 20, 1997.
This research was supported by NIH grant GM26221.
Send reprint requests to: Dr. Thomas R. Tephly, 2-452 Bowen Science Building, Department of Pharmacology, University of Iowa, Iowa City, IA 52242. E-mail: Thomas-Tephly{at}uiowa.edu.
| |
Abbreviations |
|---|
Abbreviations used are: UGT, UDP-glucuronosyltransferase; UGT2B7Y, UGT2B7(Y268); UGT2B7H, UGT2B7(H268); UDP-GlcUA, UDP-glucuronic acid; NSAID, non-steroid anti-inflammatory drug.
| |
References |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
This article has been cited by other articles:
|
|
 |
|
  H. S. Smith Opioid Metabolism Mayo Clin. Proc., July 1, 2009; 84(7): 613 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Blevins-Primeau, D. Sun, G. Chen, A. K. Sharma, C. J. Gallagher, S. Amin, and P. Lazarus Functional Significance of UDP-Glucuronosyltransferase Variants in the Metabolism of Active Tamoxifen Metabolites Cancer Res., March 1, 2009; 69(5): 1892 - 1900. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Sten, I. Bichlmaier, T. Kuuranne, A. Leinonen, J. Yli-Kauhaluoma, and M. Finel UDP-Glucuronosyltransferases (UGTs) 2B7 and UGT2B17 Display Converse Specificity in Testosterone and Epitestosterone Glucuronidation, whereas UGT2A1 Conjugates Both Androgens Similarly Drug Metab. Dispos., February 1, 2009; 37(2): 417 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Uchaipichat, A. Galetin, J. B. Houston, P. I. Mackenzie, J. A. Williams, and J. O. Miners Kinetic Modeling of the Interactions between 4-Methylumbelliferone, 1-Naphthol, and Zidovudine Glucuronidation by UDP-Glucuronosyltransferase 2B7 (UGT2B7) Provides Evidence for Multiple Substrate Binding and Effector Sites Mol. Pharmacol., October 1, 2008; 74(4): 1152 - 1162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Shiratani, M. Katoh, M. Nakajima, and T. Yokoi Species Differences in UDP-Glucuronosyltransferase Activities in Mice and Rats Drug Metab. Dispos., September 1, 2008; 36(9): 1745 - 1752. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Schulze, J. Lundmark, M. Garle, I. Skilving, L. Ekstrom, and A. Rane Doping Test Results Dependent on Genotype of Uridine Diphospho-Glucuronosyl Transferase 2B17, the Major Enzyme for Testosterone Glucuronidation J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2500 - 2506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ohno, K. Kawana, and S. Nakajin Contribution of UDP-Glucuronosyltransferase 1A1 and 1A8 to Morphine-6-Glucuronidation and Its Kinetic Properties Drug Metab. Dispos., April 1, 2008; 36(4): 688 - 694. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Bowalgaha, D. J. Elliot, P. I. Mackenzie, K. M. Knights, and J. O. Miners The Glucuronidation of {Delta}4-3-Keto C19- and C21-Hydroxysteroids by Human Liver Microsomal and Recombinant UDP-glucuronosyltransferases (UGTs): 6{alpha}- and 21-Hydroxyprogesterone Are Selective Substrates for UGT2B7 Drug Metab. Dispos., March 1, 2007; 35(3): 363 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sten, S. Qvisen, P. Uutela, L. Luukkanen, R. Kostiainen, and M. Finel Prominent but Reverse Stereoselectivity in Propranolol Glucuronidation by Human UDP-Glucuronosyltransferases 1A9 and 1A10 Drug Metab. Dispos., September 1, 2006; 34(9): 1488 - 1494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Bernard, J. Tojcic, K. Journault, L. Perusse, and C. Guillemette Influence of Nonsynonymous Polymorphisms of UGT1A8 and UGT2B7 Metabolizing Enzymes on the Formation of Phenolic and Acyl Glucuronides of Mycophenolic Acid Drug Metab. Dispos., September 1, 2006; 34(9): 1539 - 1545. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Uchaipichat, P. I. Mackenzie, D. J. Elliot, and J. O. Miners SELECTIVITY OF SUBSTRATE (TRIFLUOPERAZINE) AND INHIBITOR (AMITRIPTYLINE, ANDROSTERONE, CANRENOIC ACID, HECOGENIN, PHENYLBUTAZONE, QUINIDINE, QUININE, AND SULFINPYRAZONE) "PROBES" FOR HUMAN UDP-GLUCURONOSYLTRANSFERASES Drug Metab. Dispos., March 1, 2006; 34(3): 449 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Thibaudeau, J. Lepine, J. Tojcic, Y. Duguay, G. Pelletier, M. Plante, J. Brisson, B. Tetu, S. Jacob, L. Perusse, et al. Characterization of Common UGT1A8, UGT1A9, and UGT2B7 Variants with Different Capacities to Inactivate Mutagenic 4-Hydroxylated Metabolites of Estradiol and Estrone Cancer Res., January 1, 2006; 66(1): 125 - 133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Poppenberger, S. Fujioka, K. Soeno, G. L. George, F. E. Vaistij, S. Hiranuma, H. Seto, S. Takatsuto, G. Adam, S. Yoshida, et al. From the Cover: The UGT73C5 of Arabidopsis thaliana glucosylates brassinosteroids PNAS, October 18, 2005; 102(42): 15253 - 15258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Di Marco, M. D'Antoni, S. Attaccalite, P. Carotenuto, and R. Laufer DETERMINATION OF DRUG GLUCURONIDATION AND UDP-GLUCURONOSYLTRANSFERASE SELECTIVITY USING A 96-WELL RADIOMETRIC ASSAY Drug Metab. Dispos., June 1, 2005; 33(6): 812 - 819. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-f. Lin, W.-c. Guo, J.-g. Chen, Y.-q. Qin, K. Golka, C.-q. Xiang, Q.-w. Ma, D.-r. Lu, and J.-h. Shen An Association of UDP-Glucuronosyltransferase 2B7 C802T (His268Tyr) Polymorphism with Bladder Cancer in Benzidine-Exposed Workers in China Toxicol. Sci., May 1, 2005; 85(1): 502 - 506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kaji and T. Kume REGIOSELECTIVE GLUCURONIDATION OF DENOPAMINE: MARKED SPECIES DIFFERENCES AND IDENTIFICATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE ISOFORM Drug Metab. Dispos., March 1, 2005; 33(3): 403 - 412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kasai, T. Sakaki, R. Shinkyo, S.-i. Ikushiro, T. Iyanagi, M. Kamao, T. Okano, M. Ohta, and K. Inouye SEQUENTIAL METABOLISM OF 2,3,7-TRICHLORODIBENZO-P-DIOXIN (2,3,7-triCDD) BY CYTOCHROME P450 AND UDP-GLUCURONOSYLTRANSFERASE IN HUMAN LIVER MICROSOMES Drug Metab. Dispos., August 1, 2004; 32(8): 870 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Court, Q. Hao, S. Krishnaswamy, T. Bekaii-Saab, A. Al-Rohaimi, L. L. von Moltke, and D. J. Greenblatt UDP-Glucuronosyltransferase (UGT) 2B15 Pharmacogenetics: UGT2B15 D85Y Genotype and Gender Are Major Determinants of Oxazepam Glucuronidation by Human Liver J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 656 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Wells, P. I. Mackenzie, J. Roy Chowdhury, C. Guillemette, P. A. Gregory, Y. Ishii, A. J. Hansen, F. K. Kessler, P. M. Kim, N. Roy Chowdhury, et al. GLUCURONIDATION AND THE UDP-GLUCURONOSYLTRANSFERASES IN HEALTH AND DISEASE Drug Metab. Dispos., March 1, 2004; 32(3): 281 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ohno, Y. Saito, N. Hanioka, H. Jinno, M. Saeki, M. Ando, S. Ozawa, and J.-i. Sawada INVOLVEMENT OF HUMAN HEPATIC UGT1A1, UGT2B4, AND UGT2B7 IN THE GLUCURONIDATION OF CARVEDILOL Drug Metab. Dispos., February 1, 2004; 32(2): 235 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Wiener, J.-L. Fang, N. Dossett, and P. Lazarus Correlation between UDP-Glucuronosyltransferase Genotypes and 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone Glucuronidation Phenotype in Human Liver Microsomes Cancer Res., February 1, 2004; 64(3): 1190 - 1196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Wiener, D. R. Doerge, J.-L. Fang, P. Upadhyaya, and P. Lazarus CHARACTERIZATION OF N-GLUCURONIDATION OF THE LUNG CARCINOGEN 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANOL (NNAL) IN HUMAN LIVER: IMPORTANCE OF UDP-GLUCURONOSYLTRANSFERASE 1A4 Drug Metab. Dispos., January 1, 2004; 32(1): 72 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. N. Stone, P. I. Mackenzie, A. Galetin, J. B. Houston, and J. O. Miners ISOFORM SELECTIVITY AND KINETICS OF MORPHINE 3- AND 6-GLUCURONIDATION BY HUMAN UDP-GLUCURONOSYLTRANSFERASES: EVIDENCE FOR ATYPICAL GLUCURONIDATION KINETICS BY UGT2B7 Drug Metab. Dispos., September 1, 2003; 31(9): 1086 - 1089. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Court, S. Krishnaswamy, Q. Hao, S. X. Duan, C. J. Patten, L. L. von Moltke, and D. J. Greenblatt EVALUATION OF 3'-AZIDO-3'-DEOXYTHYMIDINE, MORPHINE, AND CODEINE AS PROBE SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 2B7 (UGT2B7) IN HUMAN LIVER MICROSOMES: SPECIFICITY AND INFLUENCE OF THE UGT2B7*2 POLYMORPHISM Drug Metab. Dispos., September 1, 2003; 31(9): 1125 - 1133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Soars, B. J. Ring, and S. A. Wrighton THE EFFECT OF INCUBATION CONDITIONS ON THE ENZYME KINETICS OF UDP-GLUCURONOSYLTRANSFERASES Drug Metab. Dispos., June 1, 2003; 31(6): 762 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Girard, O. Barbier, G. Veilleux, M. El-Alfy, and A. Belanger Human Uridine Diphosphate-Glucuronosyltransferase UGT2B7 Conjugates Mineralocorticoid and Glucocorticoid Metabolites Endocrinology, June 1, 2003; 144(6): 2659 - 2668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Turgeon, S. Chouinard, P. Belanger, S. Picard, J.-F. Labbe, P. Borgeat, and A. Belanger Glucuronidation of arachidonic and linoleic acid metabolites by human UDP-glucuronosyltransferases J. Lipid Res., June 1, 2003; 44(6): 1182 - 1191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Turgeon, J.-S. Carrier, S. Chouinard, and A. Belanger Glucuronidation Activity of the UGT2B17 Enzyme toward Xenobiotics Drug Metab. Dispos., May 1, 2003; 31(5): 670 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hirota, I. Ieiri, H. Takane, H. Sano, K. Kawamoto, H. Aono, A. Yamasaki, H. Takeuchi, M. Masada, E. Shimizu, et al. Sequence Variability and Candidate Gene Analysis in Two Cancer Patients with Complex Clinical Outcomes During Morphine Therapy Drug Metab. Dispos., May 1, 2003; 31(5): 677 - 680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. J. Bouwmeester, J. N. van den Anker, W. C. J. Hop, K. J. S. Anand, and D. Tibboel Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants Br. J. Anaesth., May 1, 2003; 90(5): 642 - 652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. V. Iyer, M. N. Ho, W. M. Shinn, W. W. Bradford, M. J. Tanga, S. S. Nath, and C. E. Green Glucuronidation of 1'-Hydroxyestragole (1'-HE) by Human UDP-Glucuronosyltransferases UGT2B7 and UGT1A9 Toxicol. Sci., May 1, 2003; 73(1): 36 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Armstrong and K. L. Cozza Pharmacokinetic Drug Interactions of Morphine, Codeine, and Their Derivatives: Theory and Clinical Reality, Part I Psychosomatics, April 1, 2003; 44(2): 167 - 171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Coffman, W. R. Kearney, S. Goldsmith, B. M. Knosp, and T. R. Tephly Opioids Bind to the Amino Acids 84 to 118 of UDP-Glucuronosyltransferase UGT2B7 Mol. Pharmacol., February 1, 2003; 63(2): 283 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Tang, J. H. Hochman, B. Ma, R. Subramanian, and K. P. Vyas Acyl Glucuronidation and Glucosidation of a New and Selective Endothelin ETA Receptor Antagonist in Human Liver Microsomes Drug Metab. Dispos., January 1, 2003; 31(1): 37 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. R. Rios and T. R. Tephly Inhibition and Active Sites of UDP-Glucuronosyltransferases 2B7 and 1A1. Drug Metab. Dispos., December 1, 2002; 30(12): 1364 - 1367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Court, S. X. Duan, C. Guillemette, K. Journault, S. Krishnaswamy, L. L. von Moltke, and D. J. Greenblatt Stereoselective Conjugation of Oxazepam by Human UDP-Glucuronosyltransferases (UGTs): S-Oxazepam Is Glucuronidated by UGT2B15, While R-Oxazepam Is Glucuronidated by UGT2B7 and UGT1A9 Drug Metab. Dispos., November 1, 2002; 30(11): 1257 - 1265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Toide, Y. Takahashi, H. Yamazaki, Y. Terauchi, T. Fujii, A. Parkinson, and T. Kamataki Hepatocyte Nuclear Factor-1alpha Is a Causal Factor Responsible for Interindividual Differences in the Expression of UDP-Glucuronosyltransferase 2B7 mRNA in Human Livers Drug Metab. Dispos., June 1, 2002; 30(6): 613 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. T. Ethell, S. Ekins, J. Wang, and B. Burchell Quantitative Structure Activity Relationships for the Glucuronidation of Simple Phenols by Expressed Human UGT1A6 and UGT1A9 Drug Metab. Dispos., June 1, 2002; 30(6): 734 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Fang, F. A. Beland, D. R. Doerge, D. Wiener, C. Guillemette, M. M. Marques, and P. Lazarus Characterization of Benzo(a)pyrene-trans-7,8-dihydrodiol Glucuronidation by Human Tissue Microsomes and Overexpressed UDP-glucuronosyltransferase Enzymes Cancer Res., April 1, 2002; 62(7): 1978 - 1986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Gestl, M. D. Green, D. A. Shearer, E. Frauenhoffer, T. R. Tephly, and J. Weisz Expression of UGT2B7, a UDP-Glucuronosyltransferase Implicated in the Metabolism of 4-Hydroxyestrone and All-Trans Retinoic Acid, in Normal Human Breast Parenchyma and in Invasive and in Situ Breast Cancers Am. J. Pathol., April 1, 2002; 160(4): 1467 - 1479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Zheng, J. Y. Park, C. Guillemette, S. P. Schantz, and P. Lazarus Tobacco Carcinogen-Detoxifying Enzyme UGT1A7 and Its Association With Orolaryngeal Cancer Risk J Natl Cancer Inst, September 19, 2001; 93(18): 1411 - 1418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Coffman, W. R. Kearney, M. D. Green, R. G. Lowery, and T. R. Tephly Analysis of Opioid Binding to UDP-Glucuronosyltransferase 2B7 Fusion Proteins Using Nuclear Magnetic Resonance Spectroscopy Mol. Pharmacol., June 1, 2001; 59(6): 1464 - 1469. [Abstract] [Full Text]
|
|
|
|
|
|
C. King, W. Tang, J. Ngui, T. Tephly, and M. Braun Characterization of Rat and Human UDP-Glucuronosyltransferases Responsible for the in Vitro Glucuronidation of Diclofenac Toxicol. Sci., May 1, 2001; 61(1): 49 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Innocenti, L. Iyer, J. Ramírez, M. D. Green, and M. J. Ratain Epirubicin Glucuronidation Is Catalyzed by Human UDP-Glucuronosyltransferase 2B7 Drug Metab. Dispos., April 13, 2001; 29(5): 686 - 692. [Abstract] [Full Text]
|
|
|
|
|
|
R. H. Tukey and C. P. Strassburg Genetic Multiplicity of the Human UDP-Glucuronosyltransferases and Regulation in the Gastrointestinal Tract Mol. Pharmacol., March 1, 2001; 59(3): 405 - 414. [Abstract] [Full Text]
|
|
|
|
|
|
M. G. Soars, R. J. Riley, K. A. B. Findlay, M. J. Coffey, and B. Burchell Evidence for Significant Differences in Microsomal Drug Glucuronidation by Canine and Human Liver and Kidney Drug Metab. Dispos., February 1, 2001; 29(2): 121 - 126. [Abstract] [Full Text]
|
|
|
|
|
|
D. Turgeon, J.-S. Carrier, E. Levesque, D. W. Hum, and A. Belanger Relative Enzymatic Activity, Protein Stability, and Tissue Distribution of Human Steroid-Metabolizing UGT2B Subfamily Members Endocrinology, February 1, 2001; 142(2): 778 - 787. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Barbier, H. Lapointe, M. El Alfy, D. W. Hum, and A. Bélanger Cellular Localization of Uridine Diphosphoglucuronosyltransferase 2B Enzymes in the Human Prostate by in Situ Hybridization and Immunohistochemistry J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4819 - 4826. [Abstract] [Full Text]
|
|
|
|
|
|
Q. Ren, S. E. Murphy, Z. Zheng, and P. Lazarus O-Glucuronidation of the Lung Carcinogen 4-(methylnitrosamino)-1- (3-Pyridyl)-1-Butanol (nnal) by Human Udp-Glucuronosyltransferases 2b7 and 1a9 Drug Metab. Dispos., November 1, 2000; 28(11): 1352 - 1360. [Abstract] [Full Text]
|
|
|
|
|
|
P. Lautala, B. T. Ethell, J. Taskinen, and B. Burchell The Specificity of Glucuronidation of Entacapone and Tolcapone by Recombinant Human Udp-Glucuronosyltransferases Drug Metab. Dispos., November 1, 2000; 28(11): 1385 - 1389. [Abstract] [Full Text]
|
|
|
|
|
|
P. J. Czernik, J. M. Little, G. W. Barone, J.-P. Raufman, and A. Radominska-Pandya Glucuronidation of Estrogens and Retinoic Acid and Expression of UDP-Glucuronosyltransferase 2B7 in Human Intestinal Mucosa Drug Metab. Dispos., October 1, 2000; 28(10): 1210 - 1216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Innocenti, W. M. Stadler, L. Iyer, J. Ramírez, E. E. Vokes, and M. J. Ratain Flavopiridol Metabolism in Cancer Patients Is Associated with the Occurrence of Diarrhea Clin. Cancer Res., September 1, 2000; 6(9): 3400 - 3405. [Abstract] [Full Text]
|
|
|
|
|
|
C. King, B. Finley, and R. Franklin The Glucuronidation of Morphine by Dog Liver Microsomes: Identification of Morphine-6-O-Glucuronide Drug Metab. Dispos., June 1, 2000; 28(6): 661 - 663. [Abstract] [Full Text]
|
|
|
|
|
|
O. Barbier, D. Turgeon, C. Girard, M. D. Green, T. R. Tephly, D. W. Hum, and A. Bélanger 3'-azido-3'-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7) Drug Metab. Dispos., May 1, 2000; 28(5): 497 - 502. [Abstract] [Full Text]
|
|
|
|
 |
|
 V. M. Samokyszyn, W. E. Gall, G. Zawada, M. A. Freyaldenhoven, G. Chen, P. I. Mackenzie, T. R. Tephly, and A. Radominska-Pandya 4-Hydroxyretinoic Acid, a Novel Substrate for Human Liver Microsomal UDP-glucuronosyltransferase(s) and Recombinant UGT2B7 J. Biol. Chem., March 15, 2000; 275(10): 6908 - 6914. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Lampe, J. Bigler, A. C. Bush, and J. D. Potter Prevalence of Polymorphisms in the Human UDP-Glucuronosyltransferase 2B Family: UGT2B4(D458E), UGT2B7(H268Y), and UGT2B15(D85Y) Cancer Epidemiol. Biomarkers Prev., March 1, 2000; 9(3): 329 - 333. [Abstract] [Full Text]
|
|
|
|
|
|
Z. Cheng, A. Radominska-Pandya, and T. R. Tephly Studies on the Substrate Specificity of Human Intestinal UDP-Glucuronosyltransferases 1A8 and 1A10 Drug Metab. Dispos., October 1, 1999; 27(10): 1165 - 1170. [Abstract] [Full Text]
|
|
|
|
|
|
N. Terrier, E. Benoit, C. Senay, F. Lapicque, A. Radominska-Pandya, J. Magdalou, and S. Fournel-Gigleux Human and Rat Liver UDP-Glucuronosyltransferases Are Targets of Ketoprofen Acylglucuronide Mol. Pharmacol., July 1, 1999; 56(1): 226 - 234. [Abstract] [Full Text]
|
|
|
|
|
|
P. A. Münzel, S. Schmohl, H. Heel, K. Kälberer, B. S. Bock-Hennig, and K. W. Bock Induction of Human UDP Glucuronosyltransferases (UGT1A6, UGT1A9, and UGT2B7) by t-Butylhydroquinone and 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Caco-2 Cells Drug Metab. Dispos., May 1, 1999; 27(5): 569 - 573. [Abstract] [Full Text]
|
|
|
|
|
|
V. Furlan, S. Demirdjian, O. Bourdon, J. Magdalou, and A.-M. Taburet Glucuronidation of Drugs by Hepatic Microsomes Derived from Healthy and Cirrhotic Human Livers J. Pharmacol. Exp. Ther., May 1, 1999; 289(2): 1169 - 1175. [Abstract] [Full Text]
|
|
|
|
 |
|
 E. M. Sellers Pharmacogenetics and Ethnoracial Differences in Smoking JAMA, July 8, 1998; 280(2): 179 - 180. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
