Received for publication October 14, 2005.
Revised January 14, 2006.
Accepted for publication January 17, 2006.

Phenobarbital treatment inhibits the formation of estradiol-dependent mammary tumors in the ACI rat

Abstract

Exposure of female ACI rats for 28 weeks to 3 mg estradiol (E₂) contained in cholesterol pellets elevated blood E₂ levels and caused palpable mammary tumors in all animals. Co-administration of phenobarbital (PB) in their drinking water reduced the incidence, number and size of MT but did not reduce blood E₂ levels. Inhibition of MT by PB was accompanied by significant changes in total hepatic metabolism of E₂ measured in vitro. PB treatment caused approximately a 4-fold increase in hepatic metabolism of E₂ in control and E₂-treated rats. The major NADPH-dependent metabolites of E₂ were 2-OH E₂ and estrone (E₁). PB, either alone or together with E₂, increased microsomal 2-hydroxylation of E₂; formation of E₁ was either unaffected or decreased slightly. PB also increased microsomal metabolism of E₂ to minor metabolites (4-OH-E₂, 6-OH-E₂, 6-OH-E₂, 14-OH-E₂, 6-keto E₁ and 2-OH-E₁) and reduced the formation of the E₂-17-oleoyl ester and the E₂- 3- and 17-glucuronides. In contrast, when given in combination with E₂, PB increased the formation of both glucuronides. Co-treatment of animals with PB and E₂ increased activities of NADP(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 E₂ including induction of E₂-hydroxylation, glucuronidation, and antioxidant defense enzymes along with inhibition of E₂ esterification in livers of female ACI rats accompany a marked reduction of E₂-dependent mammary tumors in this model.

Key words: ACI rat, CYP450, NQO1, Phenobarbital, estradiol, mammary tumors