Multiple roles of polyhalogenated biphenyls in causing increases in cytochrome P450 and uroporphyrin accumulation in cultured hepatocytes

Toxicology and Applied Pharmacology
P R SinclairJ F Sinclair

Abstract

Uroporphyrin (URO) accumulation occurs in chick embryo hepatocytes treated with a number of polyhalogenated aromatic hydrocarbons (PHAHs) that are known inducers of cytochrome P4501As (CYP1A). Previous dose response studies had shown that URO accumulation does not begin until CYP1A, as indicated by ethoxyresorufin O-deethylase (EROD) activity, is maximally induced. The reason why the concentrations of PHAHs required for URO accumulation were higher than those required to induce EROD had not been explained. PHAHs, such as 3,3',4,4'-tetrachlorobiphenyl (PCB77, IUPAC nomenclature, TCB) stimulate uroporphyrinogen (UROGEN) oxidation by microsomes from 3-methylcholanthrene (MC)-treated chick embryos. Here we used a new protocol to investigate whether the requirement for more TCB to stimulate in vitro microsomal UROGEN oxidation extended to TCB-induced URO accumulation in intact cultured hepatocytes. Cultures were treated with increasing concentrations of TCB or other PHAHs to induce CYP1As, then with cycloheximide (CX) to prevent further P450 synthesis. The CX treatment was shown to block any further increases in CYP1A as determined by immunoblots. 5-Aminolevulinic acid and a high concentration of TCB ("postinduction TCB") were then ...Continue Reading

Citations

Mar 27, 2002·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Nadia GormanPeter R Sinclair
Jul 20, 2018·Frontiers in Physiology·Kaiqin WangHongbin Li
Nov 3, 1998·Environmental Health Perspectives·A P van Birgelen
Jun 7, 2002·The Science of the Total Environment·Mark E Hahn
Nov 18, 2000·Comparative Biochemistry and Physiology. Toxicology & Pharmacology : CBP· De Catabbi SCBL C de Viale
Feb 11, 1999·Comparative Biochemistry and Physiology. Part C, Pharmacology, Toxicology & Endocrinology·M E Hahn
Feb 11, 1999·Comparative Biochemistry and Physiology. Part C, Pharmacology, Toxicology & Endocrinology·N GormanP R Sinclair
Sep 6, 2002·Chemico-biological Interactions·Mark E Hahn
May 1, 2007·Toxicology and Applied Pharmacology·Nadia GormanPeter R Sinclair

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