Hepatic enzyme induction and its potential effect on thyroid hormone metabolism in the metamorphosing tadpole of Xenopus laevis (African clawed frog)

• Published in: Journal of applied toxicology 2024-11, Vol.44 (11), p.1773-1783
• Main Authors: Wada, Kohei, Yamaguchi, Takafumi, Tanaka, Hitoshi, Fujisawa, Takuo
• Format: Article
• Language: English
• Subjects: Amphibians; Animals; beta-Naphthoflavone - pharmacology; beta-Naphthoflavone - toxicity; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Cytochromes P450; endocrine disruption; Endocrine system; Enzymatic activity; Enzyme activity; Enzyme Induction - drug effects; Enzymes; Gene expression; Glucuronosyltransferase; Glucuronosyltransferase - genetics; Glucuronosyltransferase - metabolism; hepatic enzyme induction; Juveniles; Larva - drug effects; Liver; Liver - drug effects; Liver - enzymology; Liver - metabolism; Mammals; Metamorphosis, Biological - drug effects; Naphthoflavone; Phenobarbital; Phenobarbital - pharmacology; Pregnenolone; pregnenolone carbonitrile; Pregnenolone Carbonitrile - pharmacology; Reptiles & amphibians; sodium phenobarbital; Sulfation; Sulfotransferase; Sulfotransferases - genetics; Sulfotransferases - metabolism; Thyroid; Thyroid gland; thyroid hormone; Thyroid Hormones - metabolism; Xenobiotics; Xenopus laevis; xenosensor; β‐naphthoflavone
• ISSN: 0260-437X; 1099-1263; 1099-1263
• DOI: 10.1002/jat.4672

Hepatic enzyme induction, an inherent defense system against xenobiotics, is known to simultaneously affect endocrine system functions in mammals under specific conditions, particularly thyroid hormone (TH) regulation. While this phenomenon has been studied extensively, the pathway leading to this indirect thyroid effect in mammals has unclear applicability to amphibians, despite the importance of amphibian species in assessing thyroid‐disruptive chemicals. Here, we investigated the effects of three well‐known mammalian enzyme inducers—β‐naphthoflavone (BNF), pregnenolone carbonitrile (PCN), and sodium phenobarbital (NaPB)—on the gene expression of phase‐I and phase‐II metabolizing enzymes in Xenopus laevis tadpoles. Waterborne exposure to BNF and PCN significantly induced the expression of both phase‐I (cytochrome P450, CYP) and phase‐II enzymes (UDP‐glucuronosyltransferase, UGT and sulfotransferase, SULT), but in different patterns, while NaPB exposure induced CYP2B expression without affecting phase‐II enzymes in tadpoles, in contrast to mammals. Furthermore, an ex vivo hepatic enzyme activity assay confirmed that BNF treatment significantly increased phase‐II metabolic activity (glucuronidation and sulfation) toward TH. These results suggest the potential for certain mammalian enzyme inducers to influence TH clearance in X. laevis tadpoles. Our findings provide insights into the profiles of xenosensing activity and enzyme induction in amphibians, which can facilitate a better understanding of the mechanisms of indirect effects on the thyroid system via hepatic enzyme induction in nonmammalian species. This study examined the effects of waterborne exposure to typical mammalian hepatic enzyme inducers—β‐naphthoflavone (BNF), pregnenolone carbonitrile (PCN), and sodium phenobarbital (NaPB)—on Xenopus laevis tadpoles. BNF and PCN significantly upregulated the gene expression of both phase‐I and phase‐II metabolizing enzymes in different patterns, while NaPB only induced CYP2B expression without affecting phase‐II enzymes, unlike in mammals. BNF also enhanced ex vivo phase‐II metabolic activity toward thyroid hormone (TH), suggesting hepatic enzyme induction may influence TH clearance in tadpoles.