Metabolism of the Polynuclear Sulfur Heterocycle Benzo[b]phenanthro[2,3-d]thiophene by Rodent Liver Microsomes:  Evidence for Multiple Pathways in the Bioactivation of Benzo[b]phenanthro[2,3-d]thiophene

• Published in: Chemical research in toxicology 2003-12, Vol.16 (12), p.1581-1588
• Main Authors: Yuan, Zhi-Xin, Sikka, Harish C, Munir, Sumaira, Kumar, Atul, Muruganandam, A. V, Kumar, Subodh
• Format: Article
• Language: English
• Subjects: Animals; Benz(a)Anthracenes - chemistry; Benz(a)Anthracenes - pharmacokinetics; benzo(b)phenathro(2,3-d)thiophene; Biotransformation; Carcinogens - pharmacokinetics; Cytochrome P-450 Enzyme System - metabolism; Dihydroxydihydrobenzopyrenes - chemistry; Dihydroxydihydrobenzopyrenes - pharmacokinetics; Female; Kinetics; Mice; Mice, Inbred Strains; Microsomes, Liver - metabolism; Phenanthrenes - chemistry; Phenanthrenes - pharmacokinetics; Phenols - chemistry; Phenols - metabolism; Rats; Rats, Sprague-Dawley; Spectrophotometry, Ultraviolet; Sulfones - chemistry; Sulfones - metabolism; Sulfoxides - chemistry; Sulfoxides - metabolism; Thiophenes - chemistry; Thiophenes - pharmacokinetics
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx0341310

Benzo[b]phenanthro[2,3-d]thiophene (BPT), a thia analogue of dibenz[a,h]anthracene (DBA), is a carcinogenic environmental pollutant. We have examined the metabolism of BPT by rodent liver microsomes to investigate the mechanism by which BPT produces mutagenic and carcinogenic effects. Both rat and mouse liver microsomes biotransformed [G-3H]BPT to various metabolites including BPT 3,4-diol and BPT sulfoxide, which are significantly more mutagenic than the parent compound. Liver microsomes from both control mice and rats metabolize BPT at similar rates. Treatment of mice with P450 inducers DBA, 3-methylcholanthrene (3-MC), Aroclor 1254, and phenobarbital enhanced the rate of metabolism of BPT by 74-, 28-, 77-, and 6-fold, respectively. In comparison, the treatment of rats with DBA and 3-MC increased the rate of metabolism of BPT by 22- and 34-fold, respectively, suggesting that P450 enzymes responsible for the metabolism of BPT are enhanced to different extents in rats and mice by a similar class of compounds. In general, the liver microsomes from mice treated with DBA or 3-MC were more active than those from similarly treated rats in metabolizing BPT to its 3,4-diol, a precursor to the bay-region diol epoxide of BPT. BPT sulfone was a minor metabolite (if formed) in all cases. The liver microsomes from rats treated with DBA or 3-MC or from mice treated with PB produced a significant proportion of BPT sulfoxide (12−41%). In contrast, the liver microsomes from DBA- or 3-MC-treated mice formed BPT sulfoxide as a minor metabolite (