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Vol. 26, Issue 1, 1-4, January 1998
Merck Frosst Center for Therapeutic Research
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Abstract |
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Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
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In this study, we report the effect of methanol, dimethyl sulfoxide
(DMSO), and acetonitrile on the cytochrome P450 (P450)-mediated metabolism of several substrates in human liver microsomes: phenacetin O-deethylation for P4501A2, coumarin 7-hydroxylation for
P4502A6, tolbutamide hydroxylation for P4502C8/2C9,
S-mephenytoin 4
-hydroxylation for P4502C19,
dextromethorphan O-demethylation for P4502D6, chlorzoxazone 6-hydroxylation for P4502E1, and testosterone 6
-hydroxylation for
P4503A4. DMSO was found to inhibit several P450-mediated reactions (2C8/2C9, 2C19, 2E1, and 3A4) even at low concentrations (0.2%). There
was no measurable effect on the catalytic activity of the various P450s
when methanol was present at levels 
1%, except for P4502C8/9 and
2E1. Acetonitrile did not noticeably change the catalytic activity of
the P4502C8/2C9, 2C19, 2D6, and 2E1 enzymes at concentrations 1%. It
was found that the content level of the organic solvents should be kept
lower than 1% because, for all three solvents, a concentration of 5%
strongly affected the metabolism of the various probes. These findings
should be taken into consideration when designing in vitro
metabolism studies of new chemical entities.
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Introduction |
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Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
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It has become increasingly common to use in vitro metabolism studies in liver microsomes, slices, and hepatocytes to predict in vivo biotransformations of new chemical entities. These studies include metabolite identification as well as determination of kinetic parameters such as Michaelis-Menton parameters (Km, Vmax) and inhibition constants (Ki). These studies are used for many reasons including prediction of metabolic pathways in vivo, identification of enzymes responsible for metabolism, calculation of in vivo intrinsic clearance from in vitro intrinsic clearance, and prediction of drug-drug interactions.
Many new chemical entities are highly lipophilic and require
water-miscible organic solvents for effective solubilization. It is
known that some organic solvents can affect the activity of enzymes
involved in the biotransformations of exogenous compounds. These
effects can be associated with solvation properties or competitive metabolism of the solvents for the enzyme in question. For example, it
is known that dimethyl sulfoxide (DMSO)1 is a substrate for
NADPH-dependent microsomal metabolizing enzymes (Gerhards and Gibian,
1967
) and that methanol and ethanol are substrates of the
alcohol-metabolizing enzyme systems (Teschke et al., 1975).
Several years ago, a general study on the effect of solvents on the
drug metabolism of commonly employed substrates in the Ames test was
published. It was shown that the activity of the various substrates in
the rat subcellular fractions could be inhibited or stimulated
depending on the substrate and solvent used (Kawalek and Andrews,
1980).
Cytochrome P450 (P450) enzymes play an important role in the metabolism
of exogenous compounds. It is possible to find studies that pinpoint
the effect of organic solvents on the activity of some known P450
enzymes. For example, it has been reported, using specific cytochrome
P450 substrates, that DMSO can inhibit the activity of P4502E1 and that
several organic solvents can affect the activity of P4502A6 (Yoo
et al., 1987; Draper and Parkinson, 1997). However, to our
knowledge, no systematic study clearly showing the effect of common
organic solvents on the activity of the important P450 enzymes has been
published. Such data would be valuable for the interpretation of
in vitro studies in which organic solvents are essential for
effective solubilization of the chemicals.
In this study, we report the effect of methanol, DMSO, and acetonitrile
on the cytochrome P450-mediated hepatic activity of several substrates
in human microsomes: phenacetin O-deethylation for P4501A2,
coumarin 7-hydroxylation for P4502A6, tolbutamide hydroxylation for
P4502C8/2C9, S-mephenytoin 4-hydroxylation for P4502C19,
dextromethorphan O-demethylation for P4502D6, chlorzoxazone 6-hydroxylation for P4502E1, and testosterone 6-hydroxylation for
P4503A4. The particular P450s studied were selected on the basis that
they constitute the major P450s present in human liver (Shimada
et al., 1994).
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Materials and Methods |
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Abstract
Introduction
Materials & Methods
Results & Discussion
References
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Chemicals.
-Nicotinamide adenine dinucleotide phosphate, EDTA,
D-glucose-6-phosphate, glucose 6-phosphate dehydrogenase,
acetaminophen, chlorzoxazone, coumarin, dextromethorphan, phenacetin,
tolbutamide, 7-hydroxycoumarin, and 6-hydroxychlorzoxazone were
purchased from Sigma. 6-Hydroxytestosterone and testosterone were
obtained from Steraloids (Wilton, NH). Bovine serum albumin, Folin & Ciocalteu's Phenol Reagent, and the modified Lowry protein assay
reagent were purchased from Pierce. Dextrorphan D-tartrate
and 4-hydroxytolbutamide were purchased from RBI (Natick, MA).
(±)-4-Hydroxymephenytoin and S(+)-mephenytoin were
obtained from Ultrafine Chemicals (Manchester, UK). All other reagents
were of highest purity commercially available or HPLC grade.
Tissue and Microsomes.
Human tissues were obtained from various sources (F. Guengerich,
Vanderbilt University School of Medicine, Nashville, TN; IIAM, Exton,
PA; Québec Transplant, Montréal, Canada). Microsomes were
prepared from frozen (
80°C) tissue as described in the literature (Lu and Levin, 1972). Protein concentrations of the microsomal fractions were determined by the method of Lowry et al.
(1951) using bovine serum albumin as a standard. For this study, a
human microsome mixture prepared from six different livers was used.
Enzymatic Assay.
The microsomal incubation conditions used to study the metabolism of
the phenacetin, coumarin, tolbutamide, S-mephenytoin, dextromethorphan, chlorzoxazone, and testosterone have been reported in
a previous paper (Chauret et al., 1997). Briefly, each
incubation was performed with microsomal protein in a 100 mM phosphate
buffer at pH 7.4 (except for coumarin incubations, which were conducted in 50 mM Tris) containing 20 mM glucose 6-phosphate, 2.0 mM NADP, 2.0 mM magnesium chloride, and 2.0 units of glucose 6-phosphate dehydrogenase in a total volume of 500 µl. There was a 2-min
preincubation step at 37°C, before the reaction was started by the
addition of the specific substrate.
). The
incubation mixtures were then centrifuged for 10 min at 13,000 rpm in
an Eppendorf Centrifuge 5415C. An aliquot of the supernatant fraction (injection volume of 50 µl) was analyzed by HPLC.
HPLC Analysis.
The HPLC system consisted of a Waters 600S controller, a Waters 717 plus Autosampler, a Waters 996 photodiode array detector, and a
Shimadzu RF-551 fluorescence HPLC monitor; the data were collected and
processed by Millennium version 2.15 software. The HPLC methods for the
analysis of the phenacetin-O-deethylase, coumarin-7-hydroxylase, tolbutamide hydroxylase,
S-mephenytoin 4-hydroxylase,
dextromethorphan-O-demethylase, chlorzoxazone 6-hydroxylase, and
testosterone 6-hydroxylase activities have been reported previously
(Chauret et al., 1997).
Data Analysis. Results are obtained from three different incubations and are represented as a mean ± standard deviation. In general, there was considered to be a solvent effect when the activity in the incubations containing solvents does not overlap with the activity in the controls, taking into consideration the standard deviation. The extent of inhibition or enhancement in the activity is the ratio of the average activity in the incubations containing organic solvent over the average activity in the controls containing no organic solvent, expressed in percentage.
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Results and Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
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The results of the effect of methanol, DMSO, and acetonitrile on the catalytic activity of seven cytochromes P450 are summarized in fig. 1. In all cases, there was no systematic effect of a particular solvent on the various P450s, and the various solvents did not affect the metabolism of a specific probe to the same extent.
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Overall, the phenacetin-O-deethylase P4501A2 activity (fig.
1A) was not affected by methanol or DMSO at levels 1%. In
the presence of acetonitrile at levels 1%, there was a detectable increase in the activity observed. However, at a solvent concentration of 5%, the P4501A2 activity was decreased in all cases (12, 20, and
27% inhibition for methanol, DMSO, and acetonitrile, respectively, as
compared with the control incubations).
In general, the coumarin-7-hydroxylase P4502A6 activity (fig.
1B) was not changed in the presence of methanol or DMSO in
the concentration range studied. This is in line with the findings of
Draper and Parkinson (1997). Inhibition of the activity was observed
with increasing content of acetonitrile (5-75% inhibition when
increasing the acetonitrile content from 0.2 to 5%) .
The tolbutamide hydroxylase P4502C8/2C9 activity (fig. 1C)
was not noticeably affected in the presence of 0.2% of methanol, DMSO,
or acetonitrile. However, at concentrations 
0.5%, the activity was
strongly inhibited in the presence of methanol and DMSO. When acetonitrile was present at levels up to 1%, there was no effect on
the P4502C8/9 activity, but surprisingly, the activity was enhanced in
the presence of 5% acetonitrile (139% of control). To confirm this
finding, another P4502C9 substrate, diclofenac, was used, and an
increase of activity (125% of control) was also observed in presence
of 5% acetonitrile. There are other literature examples reported for
the activation of monooxygenase reactions in liver microsomes by
chemicals (Kawalek and Andrews, 1980). For example, acetone is known to
stimulate the oxidation of acetaminophen (Moldéus and Gergely,
1980).
The S-mephenytoin 4-hydroxylase P4502C19 activity (fig.
1D) was not noticeably affected in the presence of 1%
methanol or acetonitrile. However, it was inhibited in the presence of
DMSO even at a low concentrations. At a 5% level of organic solvent, the activity was attenuated to varying degrees (39, 95, and 42% inhibition for methanol, DMSO, and acetonitrile, respectively).
Dextromethorphan-O-demethylase P4502D6 activity (fig.
1E) was not changed in the presence of 1% acetonitrile.
However, it was slightly diminished in the presence of 1% methanol
or DMSO. At a concentration of 5%, all three solvents significantly
reduced the catalytic activity of P4502D6 (35, 49, and 35% inhibition for methanol, DMSO, and acetonitrile).
Chlorzoxazone 6-hydroxylase P4502E1 activity (fig. 1F) was
slightly increased by 0.2% acetonitrile (13% enhancement as compared with control) and significantly inhibited at 5% acetonitrile (40% inhibition). Methanol did not affect the P4502E1 activity at 0.2%, but
inhibition of the activity was seen at concentrations 0.5%. Finally,
DMSO strongly inhibited the activity, even at levels as low as 0.2%
(60% inhibition). This is consistent with the fact that DMSO is a
P4502E1 inhibitor (Yoo et al., 1987).
Testosterone 6-hydroxylase P4503A4 activity (fig. 1G)
could not be evaluated in the absence of organic solvent. The results obtained with the control incubations containing no organic solvent were irreproducible and indicated an extent of metabolism that was very
low [<0.5 nmol/(mg·min)]. A possible explanation is that testosterone does not resolubilize upon addition of the preincubated mixture containing the microsomes and the incubation buffer. Based on
the results obtained with 0.2% methanol (highest activity seen), it
seems that the P4503A4 activity was not significantly modified by the
presence of methanol and acetonitrile when present at levels 0.5%.
However, the presence of DMSO, even at 0.2%, strongly reduced the
activity (32% inhibition). In all cases, the 5% organic solvent content strongly diminished the activity (30, 85, and 71% inhibition for methanol, DMSO, and acetonitrile, respectively).
As demonstrated here and by others, the presence of organic solvents
can greatly affect the in vitro metabolism of a variety of
enzymatic activities (Kawalek and Andrews, 1980; Yoo et al., 1987; Draper and Parkinson, 1997). Although DMSO is a good universal organic solvent, it is not an optimal solvent because it can inhibit the activity of several P450s (2C19, 3A4, 2E1, and 2C8/9) even at low
levels (0.2%). In general, methanol and acetonitrile represent better
alternatives as long as the content is kept at a relatively low level.
It was found that the content should be kept lower than 1%, as, in
general, with all the three solvents studied, a concentration of 5%
strongly affected the metabolism of the various probes studied. It is
important to mention that the effects observed could vary with the
experimental conditions such as the protein content in the microsomal
incubations, especially if the inhibition is due to competitive
metabolism of the solvents.
The presence of an organic solvent can strongly affect the reliability and interpretation of in vitro data. For example, if the solvent selected for in vitro studies inhibits particular P450s, one might miss an important metabolic pathway of a new compound. Also, if the rate of metabolism is affected by the solvent, the kinetic data generated by in vitro studies will be erroneous and prediction of in vivo intrinsic clearance will not be accurate. If, for an inhibition study, the organic solvents used to solubilize the substrate and the inhibitor are not kept minimal and constant, this may result in a nonspecific and/or a nonsensitive inhibition assay. This study has shown that the selection and amount of solvent for effective solubilization of chemicals is a critical parameter to consider when designing in vitro metabolism studies of new chemical entities.
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Footnotes |
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Received August 28, 1997; accepted October 14, 1997.
Send reprint requests to: Nathalie Chauret, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire Dorval, Quebec H9R 4P8, Canada.
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Abbreviations |
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Abbreviations used are: P450, cytochrome P450; DMSO, dimethyl sulfoxide.
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References |
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Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
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