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KW Bock, H Gschaidmeier, A Seidel, S Baird and B Burchell
Institute of Toxicology, University of Tubingen, Germany.
Mono- and diphenols of chrysene and benzo(a)pyrene are suspected substrates of a 3-methylcholanthrene (MC)-inducible phenol UDP- glucuronosyltransferase (UGT1A1). Mono- and diglucuronide formation from these compounds was studied in two systems, (a) livers of MC- treated rats (homologous expression) and (b) a Chinese hamster lung fibroblast cell line (V79) containing rat UGT1A1 cDNA and stably expressing this isozyme (heterologous expression). In liver microsomes of MC-treated rats, glucuronidation of 6-hydroxychrysene was stimulated 11-fold by MC treatment. With 3,6-dihydroxychrysene, formation of its 3- hydroxy-6-monoglucuronide and of the diglucuronide was increased 24- and 310-fold, respectively. Induction factors obtained for monoglucuronide formation (but not for diglucuronide formation) were in line with published data on the increase of immunodetectable UGT1A1 protein and of its mRNA. It is suggested that the high induction factors for diglucuronide formation are the result of a combination of the induction of UGT1A1 and facilitated interaction of neighboring UGT1A1 molecules in endoplasmic reticulum membranes. Glucuronidation of 6-hydroxychrysene, 3-hydroxybenzo(a)pyrene, and 3,6- dihydroxybenzo(a)pyrene to their mono- and diglucuronides was clearly detectable in V79 cells expressing UGT1A1. However, conjugation of 3,6- dihydroxychrysene to its monoglucuronides was low and diglucuronide formation was not detectable, suggesting that UGT isozymes other than UGT1A1 are responsible for these reactions.
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