Effect of oestradiol on the in vitro metabolism of 7,12-dimethylbenz(a)anthracene and its hydroxymethyl derivatives

It is known that epoxides are intermediates in the conversion of aromatic hydrocarbons into dihydrodiols, phenolic metabolites and GSH conjugates. The effect of oestradiol, in vitro , on the metabolic conversion of 7,12-dimethylbenz[a]anthracene, 7-hydroxymethyl-12-methylbenz[a]anthracene and 12-hydroxymethyl-7-methylbenz[a]-anthracene into these derivatives by a system containing NADPH, GSH and the microsomal and dialysed soluble fractions of female rat-liver has been investigated. The amounts of all three types of metabolites formed are much reduced by the presence of oestradiol and it is likely that the steroid acts by reducing the amounts of epoxide intermediates formed rather than by inhibiting the various reactions concerned in their further metabolism. This is supported by the finding that oestradiol also reduces the total amount of each substrate metabolized. Cyclohexene oxide, an inhibitor of the conversion of epoxides into dihydrodiols by the enzyme “epoxide hydrase”, greatly reduces the amount of dihydrodiols formed, but is without effect on the amounts of substrate metabolized. Furthermore, although the omission of GSH and soluble liver fraction from reaction mixtures prevents the synthesis of GSH conjugates, it does not reduce the amount of substrate metabolized, an effect that differs from that produced by oestradiol.