Metabolic activation of dibenzo(a,h)anthracene and its dihydrodiols to bacterial mutagens.

Abstract

Dibenzo(a,n)anthracene and the three metabolically possible frans-dihydrodiols of dibenzo(a,/>)anthracene were tested for mutagenicity toward Salmonella typhimurium strain TA 100 in the presence of hepatic microsomesfromAroclor1254-pretreatedrats or the cytochrome P-450-dependent monooxygenase system isolated and purifiedto near homogeneityfrom these microsomes.With either enzyme system frans-3,4-dihydroxy-3,4-dihydrodibenzo(a,h)anthracenewas activated to productsthat were more mutagenicto the bacteria than were the metabolites of dibenzo(a,/))anthracene or the metabolites of the 1,2and 5,6-dihydrodiolsof dibenzo(a,/>)anthracene.With mi crosomes but not with the purified monooxygenase sys tem, trans-5,6-dihydroxy-5,6-dihydrodibenzo(a,/))anthracene was also activated to products that were highly mutagenicto the bacteria. However, significantactivation was seen only when high concentrations of frans-5,6-dihydroxy-5,6-dihydrodibenzo(a,/i)anthracene were incu bated with relatively high amounts of enzyme. Saturation of the double bond at position 1,2 of trans-3,4-dihydroxy3,4-dihydrodibenzo(a,h)anthracene produced a tetrahydrodiol that was poorly activated in the presence of either microsomes or the purified monooxygenase sys tem. The high activity of trans-3,4-dihydroxy-3,4-dihydrodibenzo(a,/i)anthracene in both metabolic activation sys tems and the importance of the double bond in 1,2-position of the dihydrodiol strongly suggest that a bay-region 3,4-diol-1,2-epoxide is a biologically important active metabolite of dibenzo(a,/i)anthracene, thereby providing support for the bay region theory.