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ARTICLES: Yoshihisa Kato, Shin-ichi Ikushiro, Rie Takiguchi, Koichi Haraguchi, Nobuyuki Koga, Shinya Uchida, Toshiyuki Sakaki, Shizuo Yamada, Jun Kanno, and Masakuni Degawa A Novel Mechanism for Polychlorinated Biphenyl-Induced Decrease in Serum Thyroxine Level in Rats Drug Metab Dispos 2007; 35: 1949-1955 [Abstract] [Full text] [PDF]

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Possible Role of Hepatic Transporter Up-regulation in the PCB-Induced Decrease of T4 Serum Level

Harvey Wong   (10 October 2007)

Response to Wong Letter

Yoshihisa Kato, Shin-ichi Ikushiro, Rie Takiguchi, Koichi Haraguchi, Nobuyuki Koga, Shinya Uchida, Toshiyuki Sakaki, Shizuo Yamada, Jun Kanno, and Masakuni Degawa   (10 October 2007)

Possible Role of Hepatic Transporter Up-regulation in the PCB-Induced Decrease of T4 Serum Level 10 October 2007
Harvey Wong Genentech, Inc. Send letter to journal: Re: Possible Role of Hepatic Transporter Up-regulation in the PCB-Induced Decrease of T4 Serum Level wong.harvey{at}gene.com Harvey Wong	To the Editor: I read with interest the article by Kato and colleagues (2007) titled “A novel mechanism for polychlorinated biphenyls-induced decrease in serum thyroxine level in rats” in which the authors investigated several mechanisms by which Kaneclor-500 (KC500), a commercial polychlorinated biphenyl (PCB) mixture, decreased thyroxine (T4) serum levels in rats. The enhancement of thyroid hormone metabolism by PCB via induction of UDP- glucuronosyltransferases (UGTs) involved in T4 elimination was examined using Wistar and UGT1A deficient Gunn rats. KC500 treatment (10 mg/kg ip for 10 days) resulted in an increase in UGT1A expression in Wistar rats, but not Gunn rats. Despite having non-existent levels of UGT1A (as measured by Western blot), T4 serum levels decreased and T4 total body clearance increased in Gunn rats to a similar magnitude as Wistar rats. The involvement of hepatic type-I iodothyonine deiodinase activity in this observed increase in T4 total body clearance was unlikely since KC500 was shown to decreased hepatic type-I iodothyonine deiodinase activity in a previous study by the authors (Kato et al., 2004). In addition, 7- benzyloxyresorufin O-dealkylase, 7-pentoxyresorufin O-dealkylase, and 7- ethoxyresorufin O-dealkylase activities following KC500 treatment were significantly increased in both strains of rat. The magnitude of increase in the activities of these P450 substrates was greater in Wistar than in Gunn rats. The impact of KC500 on T4 distribution was also investigated in serum protein binding and tissue distribution studies using [125I] T4. KC500 treatment caused significant decreases in T4 binding to serum transthyretin (TTR). In contrast, T4 binding to serum albumin increased. Overall, these alterations in serum protein binding resulted in a significant increase in T4 unbound fraction for Wistar rats, but not for Gunn rats. In tissue distribution studies, KC500 treatment caused an increased uptake/ accumulation of [125I] T4 particularly in the liver of both strains of rat. Decreases in serum T4 levels were attributed mainly to this enhanced liver uptake/ accumulation of T4 rather than an induction of hepatic T4 UGTs. The authors concluded by speculating that the enhanced uptake/ accumulation of T4 in liver was due to changes in T4 distribution related to a PCB- and its metabolite(s)-mediated inhibition of T4 binding to TTR. In addition to inhibition of T4 binding to TTR, I would like to provide an additional point of discussion on the mechanism of the enhanced hepatic uptake of T4 and perhaps provide an additional avenue of investigation that may be considered by the authors. Alterations in T4 serum levels in rats due to the accumulation/ enhanced uptake of T4 in the liver has been observed following treatment of compounds such as SK&F 93479 (lupitidine), SK&F 93944 (temelastine) (Poole et al. 1989, 1990), and DMP 904 (Wong et. al., 2004). DMP 904 treatment resulted in an increase in T4 total body clearance accompanied by an increase in volume of distribution. Small alterations in T4 serum unbound fraction due to DMP 904 were observed, but could not account for the magnitude of the change in T4 total body clearance in rats. A substantial portion of the increase in total body clearance was due to an increase in biliary clearance of unconjugated T4. Consistent with the observed increase in biliary clearance, a whole body autoradiography study showed that DMP 904 treatment resulted in an increase in accumulation of T4 in both the liver and small intestine. In addition, DMP 904 appeared to increase expression of Oatp2, a hepatic transporter involved in T4 transport. Overall, the effects of DMP 904 on T4 homeostasis appeared to be in large part related to activation of CAR and PXR followed by up-regulation of hepatic transporters involved in T4 transport (Wong et al., 2004). Although differing in magnitude, similarities exist in the effects of KC500 and DMP 904 on T4 disposition in rats. Both compounds caused a concurrent increase in T4 total body clearance and volume of distribution, and enhanced T4 liver accumulation. Similar to DMP 904, KC500 treatment resulted in an increased concentration of [125I] T4 in the small intestines of Wistar and Gunn rats consistent with increases in biliary clearance. In particular, for UGT1A deficient Gunn rats, the T4 in the small intestine is very likely to be in the form of unconjugated T4 rather than its glucuronide metabolite. Higher levels of 7-benzyloxyresorufin O- dealkylase (CYP2B1/2 and CYP3A1/2) and 7-pentoxyresorufin O-dealkylase (CYP2B1/2) activities in Wistar and Gunn rats along with an increase in expression of UGT1A in Wistar rats suggest activation of CAR and PXR by KC500 treatment. Thus, KC500 mediated activation of CAR and PXR and subsequent up-regulation of hepatic T4 transporters may be an additional mode of action by which KC500 decreases serum T4 levels and serves as additional avenue of investigation that may be considered by the authors. In follow up experiments, measurement of mRNA and/or protein levels of hepatic T4 transporters following KC500 pretreatment in Wistar and Gunn rats may aid in clarifying the situation. I will continue to read with interest on further investigations examining the mechanism by which PCBs such as KC500 reduce T4 serum levels in rats. REFERENCES Kato Y, Ikushiro S, Takiguchi R, Haraguchi K, Koga N, Uchida S, Sakaki T, Yamada S, Kanno J and Degawa M (2007) A novel mechanism for polychlorinated biphenyls-induced decrease in serum thyroxine level in rats. Drug Metab and Disp. Doi:10.1124/dmd.107.017327. Kato Y, Ikushiro S, Haraguchi K, Yamazaki T, Ito Y, Suzuki H, Kimura R, Yamada S, Inoue T and Degawa M (2004) A possible mechanism for decrease in serum thyroxine level polychlorinated biphenyl in Wistar and Gunn rats. Tox Sci. 81: 309-315 Poole, A., Jones, R.B., Pritchard, D., Catto, L., and Leonard, T. (1989). In vitro accumulation of thyroid hormones by cultured heepatocytes and the biliary excretion of iodothyronines in rats treated with a novel histamine H2-receptor antagonist. Toxicology 59, 23-36. Poole, A., Pritchard, D., Jones, R.B., Catto, L., and Leonard, T. (1990). In vivo biliary excretion and in vitro cellular accumulation of thyroxine by rats or cultured rat hepatocytes treated with a novel histamine H1-receptor antagonist. Arch. Toxicol. 64, 474-481. Wong H, Lehman-McKeeman LD, Grubb MF, Grossman SJ, Bhaskaran VM, Solon EG, Shen HSL, Gerson RJ, Car BD, Zhao B, and Gemzik B (2004) Increased hepatobiliary clearance of unconjugated thyroxine determines DMP904-induced alterations in thyroid hormone homeostasis in rats. Tox Sci. 84: 232-242.
Response to Wong Letter 10 October 2007
Yoshihisa Kato Tokushima Bunri University, Shin-ichi Ikushiro, Rie Takiguchi, Koichi Haraguchi, Nobuyuki Koga, Shinya Uchida, Toshiyuki Sakaki, Shizuo Yamada, Jun Kanno, and Masakuni Degawa Send letter to journal: Re: Response to Wong Letter kato{at}kph.bunri-u.ac.jp Yoshihisa Kato, et al.	To the Editor: We would like to thank Dr. Harvey Wong for his valuable comments on our recent paper entitled "A Novel Mechanism for Polychlorinated Biphenyl- Induced Decrease in Serum Thyroxine Level in Rats" (Kato et al., 2007). In this paper, we demonstrated that consecutive treatment with Kanechlor-500 (KC500) at a relatively low dose (10 mg/kg, i.p., once daily for 10 days) resulted in a significant decrease in serum thyroxine (T4) not only in Wistar rats but also in Gunn (UGT1A-deficient) rats and further proposed a hypothesis that the polychlorinated biphenyl (PCB)- induced decrease occurs through increase in liver accumulation (transportation from serum to liver) of T4 rather than through induction of hepatic T4-UDP-glucuronosyltransferase. The hypothesis is strongly supported by the previous reports that phenobarbital (PB)-induced decrease in serum T4 level was observed in both Wistar and Gunn rats (Kato et al., 2005) and that treatment of rats with DMP904 resulted in decrease in serum T4 level through the accumulation/ enhanced uptake of T4 in the liver (Wong et al., 2005). In addition, significant increase in distribution of [125I]T4 dosed/g liver with development of liver hyperplasia was observed in KC500-treated Wistar rats, but not in the Gunn rats, suggesting that in Wistar rats, the hepatic hyperplasia is also attributed to the increase in the level of T4 in the liver. Recently, several transmembrane proteins have been identified as thyroid hormone transporters, including Na+/taurocholate cotrasporting polypeptide (Ntcp), Na+-independent organic anion transporting polypeptides (Oatp families), two L-type transporters (LAT1 and LAT2), and a monocarboxylate transporter MCT8 (Jansen et al., 2005). Therefore, as a possible mechanism for PCB-, PB-, or DMP904-induced accumulation of T4 in the liver, the chemical-mediated induction of hepatic thyroid hormone- transporters might be considered. In fact, DMP904 is reported to induce a T4 transporter Oatp2 in the liver (Wong et al., 2005). PB and 2,2',4,4',5 -pentachlorobiphenyl (PCB99) also show capacities for slightly increasing an expression level of Oatp2 through activation of CAR (Guo et al., 2002; Rausch-Derra et al., 2001). However, 3,3',4,4',5-pentachlorobiphenyl (PCB126), which shows a definite ability to decrease a level of Oatp2 (Guo et al., 2002), is known to decrease the level of serum T4 in rats (Van Birgelen et al., 1995). Therefore, an increase in expression level of Oatp2 seems unlikely sufficient to account for the increase in accumulation/ uptake of T4 in the liver. Further studies on the chemical-induced changes in the expression of hepatic T4 transporters and in hepatic other molecules responsible for transportation of T4 to the liver will be necessary to clarify an exact mechanism for PCB-induced accumulation of T4 in the liver. Likewise, the studies using the animals resistant to the PCB toxicity might be useful for understanding of mechanism for PCB-induced toxicity including decrease in level of serum thyroid hormone. REFERENCES Guo GL, Choudhuri S, and Klaassen CD (2002) Induction profile of rat organic anion transporting polypeptide 2 (oatp2) by prototypical drug- metabolizing enzyme inducers that activate gene expression through ligand- activated transcription factor pathways. J Pharmacol Exp Ther 300:206-212. Jansen J, Friesema EC, Milici C, and Visser TJ (2005) Thyroid hormone transporters in health and disease. Thyroid 15: 757-768. Kato Y, Ikushiro S, Takiguchi R, Haraguchi K, Koga N, Uchida S, Sakaki T, Yamada S, Kanno J, and Degawa M (2007) A novel mechanism for polychlorinated biphenyls-induced decrease in serum thyroxine level in rats. Drug Metab Dispos 35:1949-1955. Kato Y, Suzuki H, Ikushiro S, Yamada S, and Degawa M (2005) Decrease in serum thyroxine level by phenobarbital in rats is not necessarily dependent on increase in hepatic UDP-glucuronosyltransferase. Drug Metab Dispos 33:1608-1612. Rausch-Derra LC, Hartley DP, Meier PJ, and Klaassen CD (2001) Differential effects of microsomal enzyme-inducing chemicals on the hepatic expression of rat organic anion transporters, OATP1 and OATP2. Hepatology 33:1469-1478. Van Birgelen APJM, Smit EA, Kampen IM, Groeneveld CN, Fase KM, van der Kolk J, Poiger H, van den Berg M, Koeman JH, and Brouwer A (1995) Subchronic effects of 2,3,7,8-TCDD or PCBs on thyroid hormone metabolism: Use in risk assessment. Eur J Pharmacol 293: 77-85. Wong H, Lehman-McKeeman LD, Grubb MF, Grossman SJ, Bhaskaran VM, Solon EG, Shen HSL, Gerson RJ, Car BD, Zhao B, and Gemzik B (2005) Increased hepatobiliary clearance of unconjugated thyroxine determines DMP904-induced alterations in thyroid hormone homeostasis in rats. Tox Sci 84: 232-242.