Drug Metabolism and Disposition Fast Forward
First published on August 18, 2005; DOI: 10.1124/dmd.105.006189
0090-9556/05/3311-1661-1665$20.00
DMD 33:1661-1665, 2005
THE DECREASE IN LEVEL OF SERUM THYROXINE BY 2,2',4,5,5'-PENTACHLOROBIPHENYL IN RATS AND MICE: NO CORRELATION WITH FORMATION OF METHYLSULFONYL METABOLITES
Yoshihisa Kato,
Koichi Haraguchi,
Tomoaki Yamazaki,
Ryohei Kimura,
Nobuyuki Koga,
Shizuo Yamada, and
Masakuni Degawa
School of Pharmaceutical Sciences and COE Program in the 21st Century, University of Shizuoka, Shizuoka, Japan (Y.K., T.Y., R.K., S.Y., M.D.); Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan (K.H.); and Faculty of Nutritional Sciences, Nakamura Gakuen University, Fukuoka, Japan (N.K.)
(Received June 22, 2005;
accepted August 18, 2005)
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Abstract
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A relationship between formation of methylsulfonyl (MeSO2) metabolites of 2,2',4,5,5'-pentachlorobiphenyl (PentaCB) and decrease in serum thyroxine (T4) level was examined in the rats and mice after a single i.p. injection of PentaCB (342 µmol/kg body weight). In either rats or mice, levels of the 3- and 4-MeSO2 metabolites of PentaCB in the liver and feces increased in a time-dependent fashion up to 8 days after PentaCB-treatment. However, there was a marked difference between rats and mice in the amount of the metabolites formed, and the cumulative amount of the either MeSO2 metabolite for 8 days after PentaCB treatment in the liver was 4 to 15 times higher in mice than in rats. On the other hand, a 40 to 60% decrease in level of serum total T4 occurred in both rats and mice at 1 day after PentaCB treatment, and the decrease was retained up to 8 days after PentaCB treatment. Thus, there was a marked difference between rats and mice in the formation of MeSO2 metabolites from PentaCB but not a significant difference between rats and mice in PentaCB-induced decrease in the level of serum total T4, indicating that PentaCB-induced decrease in the level of serum total T4 is not necessarily dependent on the MeSO2 metabolites formed.
Polychlorinated biphenyls (PCBs) are environmental pollutants that accumulate in the food chain due to their high lipophilicity and low biotransformation rate (Safe, 1993
). Their bioaccumulation has been detected in the environment (Olafsson et al., 1987; Kannan et al., 1989) and in human serum, adipose tissue, and milk (Safe et al., 1985; Dewailly et al., 1991; Fängström et al., 2002).
A number of methylsulfonyl (MeSO2) metabolites of PCBs have been found in several species of animals in Canada, Sweden, and East Greenland (Haraguchi et al., 1992; Bergman et al., 1994; Letcher et al., 1995; Chu et al., 2003; Sandala et al., 2004) and in both healthy humans and Yusho patients in Japan (Haraguchi et al., 1986, 1989). Additionally, MeSO2-PCBs were identified in human milk, blood, liver, and adipose tissue (Norén et al., 1996; Weistrand and Norén, 1997; Weistrand et al., 1997; Guvenius et al., 2002). The main MeSO2-PCBs found are 3- and 4-MeSO2 derivatives of nonplanar PCBs (Haraguchi et al., 1992; Bergman et al., 1994; Letcher et al., 1995; Norén et al., 1996; Guvenius et al., 2002; Sandala et al., 2004).
The 3-MeSO2-PCBs derived from nonplanar PCBs, including 2,2',4,5,5'-pentachlorobiphenyl (PentaCB) 2,3',4',5-tetrachlorobiphenyl, and 2,2',3',4',5-pentachlorobiphenyl, show much greater activities for inducing hepatic drug-metabolizing enzymes than the corresponding parent PCBs (Kato et al., 1995, 1999b), whereas the 4-MeSO2-PCBs have no such capacity (Kato et al., 1995). More recently, we have found that some of MeSO2 metabolites, including 3-MeSO2- and 4-MeSO2-PentaCBs (Fig. 1), were able to reduce level of serum thyroxine (T4) and/or to increase level of serum thyroid-stimulating hormone (TSH) in rats (Kato et al., 1998, 1999a, 2000b). Furthermore, the MeSO2 metabolite-induced decrease in serum T4 level was suggested to occur, at least in part, through increase in hepatic UDP-glucuronosyltransferases (UDP-GTs) UGT1A1 and UGT1A6, responsible for glucuronidation of T4 (Kato et al., 2000a). Thus, MeSO2 metabolites of nonplanar PCBs seem to play important roles in PCB-induced toxicities.
There is a species difference in the response to PCB-induced toxicities, including induction of drug-metabolizing enzymes, endocrine disruption, carcinogenicity, and impairment of immune system (Safe, 1994). As one of reasons for the species difference, difference in a PCB metabolism would be considered.
In the present study, we examined a species difference in the in vivo metabolism of PentaCB between rats and mice and a relationship between formation of MeSO2 metabolites and decrease in level of serum total T4. The results demonstrate that there is a marked species difference in formation of MeSO2 metabolites between rats and mice, whereas no species difference in PentaCB-induced decrease in level of serum total T4 was observed, indicating that there is not necessarily correlation between formation of MeSO2 metabolites and decrease in serum total T4.
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Materials and Methods
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Chemicals. PentaCB was synthesized by using the Cadogan coupling reactions (Cadogan, 1962). 3-MeSO2- and 4-MeSO2-PentaCBs were prepared by the method as described previously (Haraguchi et al., 1987). The purity of these compounds was >99% when analyzed by gas chromatography. Panacete 810 (medium-chain triglycerides) was purchased from Nippon Oils and Fats Co. Ltd. (Tokyo, Japan). All other chemicals were obtained commercially.
Animal Treatments. Male Wistar rats, weighing 180 to 200 g, and male ddY mice, weighing 27 to 35 g, were housed in three or four per cage with free access to commercial chow and tap water and maintained on a 12-h dark/light cycle (8:00 AM-8:00 PM light) in an air-controlled room (temperature, 24.5 ± 1°C; humidity, 55 ± 5%). All animals were handled with human care under the guidelines of the University of Shizuoka (Shizuoka, Japan). Treatments of rats and mice with PentaCB were performed according to the method of Kato et al. (1995, 1999b, 2004). Briefly, the rats and mice received a single i.p. injection of PentaCB (342 µmol/5 ml/kg) dissolved in Panacete 810. In addition, control animals were treated with a vehicle alone (5 ml/kg). All animals were killed by decapitation on the designated time after the dosing, and the liver was removed and kept at –50°C until examined. Liver microsomal fractions were prepared according to the method of Kato et al. (1995) and stored at –85°C until used.
Level of Serum Thyroid Hormone T4. Blood was collected from each animal between 10:30 and 11:30 AM. After clotting at room temperature, serum was separated by centrifugation and stored at –50°C until used. The level of serum total T4 was measured by radioimmunoassays using an Amerlex-MT4 assay system (GE Healthcare, Little Chalfont, Buckinghamshire, UK).
Hepatic Microsomal T4-UDP-GT Activity. Amount of microsomal protein was determined by the method of Lowry et al. (1951) with bovine serum albumin as a standard. Activity of microsomal T4-UDP-GT was determined by the method of Barter and Klaassen (1992).
Determination of PentaCB and Its MeSO2 Metabolites. Amounts of PentaCB and its MeSO2 metabolites in the liver and feces were determined with gas chromatography as described previously (Bergman et al., 1992). In the present study, the total area under the liver concentration versus time curve was calculated by the trapezoidal rule and shown as an AUC.
Statistics. The data obtained were statistically analyzed according to Student's t test.
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Results
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MeSO2 Metabolites of PentaCB. We have previously reported that when rats and mice were treated with PentaCB (34 µmol/kg), the sum of hepatic 3- and 4-MeSO2 metabolites detected in mice was 2-fold higher than that in the rats (Haraguchi et al., 2005). To further clarify a difference between rats and mice in the level of the MeSO2 metabolites from PentaCB, we examined levels of the MeSO2 metabolites in both the liver and feces from the PentaCB (342 µmol/kg)-treated rats and mice. Amounts of PentaCB and its MeSO2 metabolites, 3- and 4-MeSO2-PentaCBs, after the PentaCB treatment in either the liver or the feces were clearly different between rats and mice. The level of PentaCB in the liver of either rats or mice reached the maximum at day 2 after the treatment and then decreased. The maximum levels in rats and mice were about 10 nmol/g tissue and about 35 nmol/g tissue, respectively. Levels of 3- and 4-MeSO2-PentaCBs in the mouse liver increased in a time-dependent fashion up to 4 days after the PentaCB treatment, and the maximum levels of 3- and 4-MeSO2-PentaCBs were about 4 nmol/g tissue and about 7 nmol/g tissue, respectively (Fig. 2). On the other hand, in the rat liver, the 3- and 4-MeSO2 metabolites were hardly produced, and levels of the metabolites were less than 1 nmol/g tissue at the any time examined. AUC values in 3- and 4-MeSO2-PentaCBs in the liver were 17.50 and 31.54 nmol · day/g tissue, respectively, in mice and 2.92 and 4.83 nmol · day/g tissue, respectively, in rats. Thus, the AUC values obtained were much higher in mice than in rats.
In feces, the level of PentaCB was higher in rats than in mice, whereas levels of 3- and 4-MeSO2 metabolites of PentaCB were much higher in mice than in rats (Fig. 3). In addition, the 3-MeSO2 metabolite was hardly detected in the rat feces.
Serum Thyroid Hormone Level. Effects of PentaCB on the level of serum thyroid hormone T4 in rats and mice were next examined. Levels of serum total T4 in both rats and mice were significantly decreased by treatment with PentaCB (Fig. 4). In either rats or mice, the level of serum total T4 decreased to 40 to 60% of the corresponding control level at day 1 after PentaCB treatment, and the decrease was maintained up to 8 days in each species of animal. In addition, no significant change in level of serum TSH after treatment with PentaCB was found in either rats or mice (data not shown).
Hepatic T4-UDP-GT Activity. We examined effects of PentaCB on hepatic T4-UDP-GT activity in rats and mice. Hepatic activities of T4-UDP-GT at day 4 after treatment with PentaCB in rats and mice increased to 2- and 1.6-fold over the corresponding control levels, respectively (Table 1).
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TABLE 1 Effects of PentaCB on hepatic T4-UDP-GT activity in rats and mice
Animals were given PentaCB (342 µmol/kg i.p.) and killed at day 4 after the treatment. Data represent the mean ± S.E. for three to six animals.
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Discussion
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We have previously reported that there are species differences between rats and mice in the levels of PentaCB and its metabolites, including methylsulfonylated and hydroxylated PentaCBs, and in their tissue distributions (Haraguchi et al., 2005). In the present study, a clear difference in the formation of MeSO2 metabolites between the PentaCB-treated rats and mice was confirmed. A possible mechanism for the formation of the sulfur-containing metabolites from PentaCB is showed in Fig. 5 (Hansen, 1999). In brief, PentaCB is first oxidized to arene oxide intermediate in the liver, and the resultant arene oxide is converted to glutathion-conjugated form by hepatic glutathione S-transferase. The glutathion conjugate is introduced to a mercapturic acid pathway and, thereafter, excreted as a cysteine conjugate into the gastrointestinal tract via the bile. C–S bond of the cysteine conjugate is cleaved to thiol form by intestinal microflora C–S lyase. The resultant thiol compound is methylated to methylsulfide form. Thereafter, the methylsulfide is oxidized to methylsulfoxide and further to methylsulfone (MeSO2 metabolites) in the liver. In addition, Koga et al. (2002) have suggested that S-oxidation of the methylsulfide is catalyzed by cytochrome P450 enzymes, especially CYP2B subfamily enzymes in rats, hamsters, and guinea pigs. Considering a possible process of formation of MeSO2 metabolites, difference between rats and mice in the amount of hepatic MeSO2 metabolites formed from PentaCB would be attributed to the difference in the activity of CYP2B subfamily enzymes, glutathione S-transferase, and/or intestinal microflora C–S lyase.
We have previously reported that 3-MeSO2 metabolite of PentaCB showed higher activity than a parent compound PentaCB for inducing hepatic drug-metabolizing enzymes (Kato et al., 1995, 1999b) and further demonstrated that some MeSO2 metabolites, including 3-MeSO2- and 4-MeSO2-PentaCBs, could reduce serum total T4 level in rats (Kato et al., 1998, 1999a, 2000b). Accordingly, it has been expected that MeSO2-PentaCB metabolites contribute to decrease in the level of serum T4 in PentaCB-treated animals. However, despite levels of MeSO2-PentaCB metabolites in both the liver and feces that were much higher in mice than in rats, magnitudes of decrease in the level of serum total T4 in rats and mice were almost the same. The present findings indicate that PentaCB-induced decrease in serum T4 level is not dependent on only the MeSO2 metabolites formed.
Decrease in the level of serum T4 by PCB has been thought to occur through increase in hepatic T4-UDP-GT activity (Barter and Klaassen, 1994; Van Birgelen et al., 1995; Schuur et al., 1997). However, it has been reported that difference between rats and mice in magnitude of decrease in level of serum total T4 by 2,2',4,4',5,5'-hexachlorobiphenyl is not well correlated with that of increase in activity of T4-UDP-GT (Craft et al., 2002). Likewise, we have reported that treatment with Kanechlor-500 resulted in a significant decrease in serum T4 level in both rats and mice, although a significant increase in the activity of T4-UDP-GT enzymes, including UGT1A1 and UGT1A6, by the PCB occurred only in rats but not in mice (Kato et al., 2003) and further demonstrated that treatment with either Kanechlor-500 or PentaCB resulted in a drastic decrease in serum total T4 level even in UGT1A1/1A6-deficient (Gunn) rats (Kato et al., 2004). These previous reports strongly propose that the decrease in serum total T4 level by PCBs including PentaCB does not occur only through increase in hepatic T4-UDP-GT activity, although significant increase in T4-UDP-GT activity by PentaCB was observed in both rats and mice (Table 1).
In the present study, level of serum TSH in either rats or mice was not significantly changed by PentaCB, indicating that TSH is not related to the PentaCB-induced decrease in serum T4 levels. In addition, it had been reported that serum TSH level was little affected by PCBs (Liu et al., 1995; Hood et al., 1999; Hallgren et al., 2001; Kato et al., 2003).
In the PentaCB-treated rats and mice, 3-OH-, 3'-OH-, 4'-OH-, and 3',4'-(OH)2-PentaCBs were found in both the liver and serum (Haraguchi et al., 2005). Mono- and dihydroxylated PCB derivatives (Lans et al., 1993; Meerts et al., 2002), including 4-OH-2,3,3',4',5-pentachlorobiphenyl, 4,4'-(OH)2-3,3',5,5'-tetrachlorobiphenyl, and 4,4'-(OH)2-2,3,3',5,5'-pentachlorobiphenyl, have been reported to bind to T4-transporting serum protein transthyretin. Therefore, PentaCB-induced decrease in the level of serum total T4 might occur, in part, through formation of the hydroxylated metabolites showing ability to bind to transthyretin.
In conclusion, we demonstrate herein that there is a marked difference between rats and mice in the formation of MeSO2 metabolites from PentaCB and further suggest that PentaCB-induced decrease in level of serum total T4 is not necessarily dependent on the formation of the MeSO2 metabolites. Additionally, the present findings demonstrate that PentaCB-induced decrease in serum total T4 level in either rats or mice occurs without increase in serum TSH level. Although the PentaCB-induced decrease might occur, at least in part, through induction of T4-UDP-GT and/or formation of the hydroxylated metabolites from PentaCB, the exact mechanism for PentaCB-induced decrease in serum thyroid hormones remains unclear. Further studies on PentaCB-induced alterations of the level and function of T4-transporters in the liver and extrahepatic tissues would be necessary for the understanding of the exact mechanism.
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Footnotes
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This work was supported in part by a Grant-in-Aid for Scientific Research (C) (no. 15510058, Y.K.; no. 16590101, K.H.; no. 17590104, M.D.) from Japan Society for the Promotion of Science, by a Health Sciences Research Grant for Research on Environmental Health (H11-Seikatsu-024, M.D.) from the Ministry of Health and Welfare of Japan, and by a Health and Labour Sciences Research Grants for Risk Analysis Research on Food and Pharmaceuticals (H13-Seikatsu-013, Y.K.) from Ministry of Health, Labour and Welfare of Japan.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.105.006189.
ABBREVIATIONS: PCB, polychlorinated biphenyl; MeSO2, methylsulfonyl; PentaCB, 2,2',4,5,5'-pentachlorobiphenyl; T4, thyroxine; TSH, thyroid-stimulating hormone; UDP-GT, UDP-glucuronosyltransferase; AUC, area under the curve.
Address correspondence to: Dr. Yoshihisa Kato, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan. E-mail: kato{at}ys7.u-shizuoka-ken.ac.jp
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Abstract
Materials and Methods
—, rats; —
—, mice.
