Phenobarbital Treatment Inhibits the Formation of Estradiol-Dependent Mammary Tumors in the August-Copenhagen Irish Rat

Abstract

Exposure of female August-Copenhagen Irish (ACI) rats for 28 weeks to 3 mg of estradiol (E(2)) contained in cholesterol pellets elevated blood E(2) levels and caused palpable mammary tumors in all animals. Coadministration of phenobarbital (PB) in their drinking water reduced the incidence, number, and size of mammary tumors (MTs) but did not reduce blood E(2) levels. Inhibition of MTs by PB was accompanied by significant changes in total hepatic metabolism of E(2) measured in vitro. PB treatment caused approximately a 4-fold increase in hepatic metabolism of E(2) in control and E(2)-treated rats. The major NAD(P)H-dependent metabolites of E(2) were 2-OH-E(2) and estrone (E(1)). PB, either alone or together with E(2), increased microsomal 2-hydroxylation of E(2); formation of E(1) was either unaffected or decreased slightly. PB also increased microsomal metabolism of E(2) to minor metabolites (4-OH-E(2), 6alpha-OH-E(2), 6beta-OH-E(2), 14alpha-OH-E(2), 6-keto E(1), and 2-OH-E(1)) and reduced the formation of the E(2)-17beta-oleoyl ester and the E(2) 3- and 17-glucuronides. In contrast, when given in combination with E(2), PB increased the formation of both glucuronides. Cotreatment of animals with PB and E(2) increased activities of NAD(P)H:quinone oxidoreductase and glutathione S-transferase to a greater extent than either compound alone. Collectively, these results show that the multiple actions of PB on hepatic metabolism of E(2), including induction of E(2) hydroxylation, glucuronidation, and antioxidant defense enzymes along with inhibition of E(2) esterification in livers of female ACI rats, accompany a marked reduction of E(2)-dependent mammary tumors in this model.