Polychlorinated Biphenyl Congeners that Increase the Glucuronidation and Biliary Excretion of Thyroxine Are Distinct from the Congeners that Enhance the Serum Disappearance of Thyroxine

Martin, L. E.; Wilson, Daniel T.; Reuhl, Kenneth R.; Gallo, Michael A.; Klaassen, Curtis D.

doi:10.1124/dmd.111.042796

Cited by 19 publications

(17 citation statements)

References 37 publications

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“…8,30,31) However, the change in hepatic T 4 -UGT activity by CB153, a PB-type inducer, does not necessarily correlate with those of serum total T 4 in either rats or mice. 10) In this study, we further demonstrated that CB118, a mixed (TCDD/PB)-type inducer, showed a definite capacity for decreasing serum total T 4 level in both C57BL/6 and DBA/2 mice, although the CB118-mediated increases in the level and activity of hepatic T 4 -UGTs, such as Ugt1a and Ugt1a1, and in the amounts of the biliary metabolite(s) including (Figs.…”

Section: Discussionmentioning

confidence: 99%

A Possible Mechanism for 2,3′,4,4′,5′-Pentachlorobiphenyl-Mediated Decrease in Serum Thyroxine Level in Mice

Kato

Onishi

Haraguchi

et al. 2013

Biological & Pharmaceutical Bulletin

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The effect of 2,3′,4,4′,5′-pentachlorobiphenyl (CB118) on serum total thyroxine (T 4 ) level was comparatively examined between C57BL/6 and DBA/2 mice, which are sensitive and insensitive, respectively, to aryl hydrocarbon receptor-mediated biological changes. After 5 d of CB118 administration (50 mg/kg, intraperitoneally (i.p.)), the serum total T 4 levels in both strains of mice were markedly decreased. However, significant decreases in serum thyroid-stimulating hormone levels were observed in DBA/2 mice, but not in C57BL/6 mice. In contrast, significant increases in the level and activity of hepatic T 4 -uridine 5′-diphosphate (UDP)-glucuronosyltransferase by CB118 treatment were observed only in C57BL/6 mice. Likewise, significant increases in the amounts of biliary Key words 2,3′,4,4′,5′-pentachlorobiphenyl; glucuronosyltransferase; thyroxine; mouse Studies on polychlorinated biphenyls (PCBs)-mediated toxicities, 1,2) such as body weight loss, endocrine disruption, teratogenicity, carcinogenicity and impairment of the reproductive and immune systems, have been performed over the last 40 years. Furthermore, Fukuoka Yusho (oil disease) and Taiwan Yucheng patients are reported to show various symptoms, such as acneform eruptions, hypersecretion of meibomian glands, hyperpigmentation of the face, and enhanced hormonal effects of thyroxine (T 4 ), eyelids, and gingival. 3,4) PCBs consist of a series of 209 individual congeners that vary in the number and position of substituent chlorine on a biphenyl structure. These are classified into three types of inducers (i.e., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-type, phenobarbital (PB)-type, and mixed (TCDD/PB)-type inducers) based on the induction pattern of hepatic drugmetabolizing enzymes, including cytochrome P450 (CYP) and uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) family enzymes.5,6) 3,3′,4,4′,5-Pentachlorobiphenyl (CB126) and 2,2′,4,4′,5,5′-hexachlorobiphenyls (CB153) are representative inducers of TCDD-type and PB-type, respectively. 5)Namely, CB126 and CB153 can induce CYP1A/UGT1A and CYP2B/UGT2B subfamily enzymes, respectively. 5,6) In contrast, 2,3′,4,4′,5′-pentachlorobiphenyl (CB118) is considered a mixed (TCDD/PB)-type inducer, 5) which can induce CYP1A, CYP2B, UGT1A and UGT2B subfamily enzymes. 5,6) In contrast, PCB congeners, including CB126, CB153, and CB118, are well known to decrease the level of serum thyroid hormone.7-10) As a possible mechanism for the PCB-mediated decrease in serum thyroid hormone, the increase in hepatic T 4 -UGTs 11) and the promotion of the release of T 4 from a complex of T 4 -serum transthyretin (TTR) by a PCB congener and its hydroxylated metabolites have been proposed. 10,[12][13][14] However, we have demonstrated that Kanechlor-500 (KC500), a commercial PCB mixture, shows an ability to decrease serum total T 4 levels through enhancement of accumulation of T 4 in several tissues, especially the liver, rather than via an increase in hepatic T 4 -UGT activity. 15) Our study also indicated that CB126-media...

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Section: Discussionmentioning

confidence: 99%

A Possible Mechanism for 2,3′,4,4′,5′-Pentachlorobiphenyl-Mediated Decrease in Serum Thyroxine Level in Mice

Kato

Onishi

Haraguchi

et al. 2013

Biological & Pharmaceutical Bulletin

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“…In rats, PCBs decrease THs and this effect is thought to be due to increased hepatic accumulation and glucuronidation (Bastomsky, 1974;Craft et al, 2002;Crofton et al, 2005;Hood & Klaassen, 2000a;Klaassen & Hood, 2001;Martin et al, 2012). PCB 153 is one of the predominate congeners found in the environment as well as in humans.…”

Section: Discussionmentioning

confidence: 99%

In vitrometabolism of thyroxine by rat and human hepatocytes

Richardson

Ferguson

Sey³

et al. 2013

Xenobiotica

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Abstract1. The liver metabolizes thyroxine (T 4 ) through two major pathways: deiodination and conjugation. Following exposure to xenobiotics, T 4 conjugation increases through the induction of hepatic uridine diphosphate glucuronosyltransferase (UGT) in rodents; however, it is uncertain to what degree different species employ deiodination and conjugation in the metabolism of T 4 . The objective of this study was to compare the metabolism of T 4 in untreated and 2,2 0 ,4,4 0 ,5,5 0 -hexachlorobiphenyl (PCB 153)-treated primary sandwich-cultured hepatocytes from rat (SCRH) and human (SCHH). 2. Basal metabolite concentrations were 13 times higher in the medium of SCRH compared to SCHH. Metabolite distribution in the medium of SCRH versus SCHH was as follows: T 4 G, (91.6 versus 5.3%); T 4 S, (3.6 versus 4.4%) and T 3 þ rT 3 , (4.9 versus 90.3%). PCB 153 induced T 4 G in the medium of SCRH and SCHH; however, T 4 S and T 3 þ rT 3 were changed but to a much lesser degree. 3. The results indicate that baseline T 4 glucuronidation is greater in SCRH compared to SCHH.These data also suggest that glucuronidation may be a more important pathway for T 4 metabolism in rats and deiodination may be a favored pathway in humans; however, with PCB 153 treatment these data support glucuronidation as a primary route of T 4 metabolism in both rat and humans.

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“…Although published reports indicate that TriBDD can exert effects in rat liver and hepatoma cells (Mason et al, 1987;Yang et al, 1983), in this study it did not affect antibody formation or Cyp1a1 gene expression. Martin et al (2012) proposed that TCDD decreases circulating T4 through increased biliary excretion (Martin et al, 2012). It has been suggested that induction of UGTs, which are AhR regulated genes (Bock and Kohle, 2009), and subsequent glucuronidation of T4 lead to increased excretion of the hormone.…”

Section: Discussionmentioning

confidence: 99%

Relative Potency for Altered Humoral Immunity Induced by Polybrominated and Polychlorinated Dioxins/Furans in Female B6C3F1/N Mice

Frawley

DeVito

Walker

et al. 2014

Toxicological Sciences

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The use of brominated flame retardants and incineration of bromine-containing materials has lead to an increase in polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) in the environment. Measurable amounts of PBDD/Fs have been detected in soil, seafood, and human breast milk and serum. Studies indicate that the relative potencies of some PBDD/Fs based on enzyme induction are equivalent to those of some polychlorinated dibenzo-p-dioxins and dibenzofurans. To assess the humoral immunity relative potencies of PBDD/Fs and compare them to their chlorinated analogs, female B6C3F1/N mice received a single oral exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrabromodibenzofuran (TBDF), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentabromodibenzofuran (1PeBDF), 1,2,3,7,8-pentachlorodibenzofuran (1PeCDF), 2,3,4,7,8-pentabromodibenzofuran (4PeBDF), 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), 2,3-dibromo-7,8-dichlorodibenzo-p-dioxin (DBDCDD), or 2,3,7-tribromodibenzo-p-dioxin (TriBDD). Inhibition of the immunoglobulin M (IgM) antibody forming cell response was measured 4 days following immunization with sheep red blood cells. The data were fit to a Hill model to estimate the ED50 for inhibition. Expression of xenobiotic metabolizing enzyme (XME) and thyroxine transport protein (Ttr) genes in liver was measured by PCR to assess aryl hydrocarbon-mediated responses. TCDD, TBDF, TCDF, 1PeBDF, 4PeBDF, 4PeCDF, and DBDCDD suppressed the IgM antibody response and Ttr gene expression, and upregulated phase I XME genes. 1PeCDF suppressed the IgM antibody response but only upregulated phase I XME genes; TriBDD had no effect on antibody response. The rank order of potency (ED50) for these chemicals was TCDD>TBDF>4PeBDF>TCDF/4PeCDF/1PeBDF>1PeCDF. Whereas TCDD was the most potent compound tested, the brominated analogs were more potent than their chlorinated analogs, suggesting that these compounds should be considered in toxic equivalency factor evaluation and risk assessment.

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Polychlorinated Biphenyl Congeners that Increase the Glucuronidation and Biliary Excretion of Thyroxine Are Distinct from the Congeners that Enhance the Serum Disappearance of Thyroxine

Cited by 19 publications

References 37 publications

A Possible Mechanism for 2,3′,4,4′,5′-Pentachlorobiphenyl-Mediated Decrease in Serum Thyroxine Level in Mice

A Possible Mechanism for 2,3′,4,4′,5′-Pentachlorobiphenyl-Mediated Decrease in Serum Thyroxine Level in Mice

In vitrometabolism of thyroxine by rat and human hepatocytes

Relative Potency for Altered Humoral Immunity Induced by Polybrominated and Polychlorinated Dioxins/Furans in Female B6C3F1/N Mice

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