TY - JOUR
T1 - Phenobarbital treatment inhibits the formation of estradiol-dependent mammary tumors in the August-Copenhagen irish rat
AU - Mesia-Vela, Sonia
AU - Sanchez, Rosa I.
AU - Reuhl, Kenneth R.
AU - Conney, Allan H.
AU - Kauffman, Frederick C.
PY - 2006/5
Y1 - 2006/5
N2 - Exposure of female August-Copenhagen Irish (ACI) rats for 28 weeks to 3 mg of estradiol (E2) contained in cholesterol pellets elevated blood E2 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 E2 levels. Inhibition of MTs 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 NAD(P)H-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, 6α-OH-E2, 6β-OH-E2, 14α-OH-E2, 6-keto E1, and 2-OH-E1) and reduced the formation of the E2-17β-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 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 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.
AB - Exposure of female August-Copenhagen Irish (ACI) rats for 28 weeks to 3 mg of estradiol (E2) contained in cholesterol pellets elevated blood E2 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 E2 levels. Inhibition of MTs 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 NAD(P)H-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, 6α-OH-E2, 6β-OH-E2, 14α-OH-E2, 6-keto E1, and 2-OH-E1) and reduced the formation of the E2-17β-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 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 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.
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U2 - https://doi.org/10.1124/jpet.105.096867
DO - https://doi.org/10.1124/jpet.105.096867
M3 - Article
C2 - 16421288
SN - 0022-3565
VL - 317
SP - 590
EP - 597
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -