This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Haaf, H. Articles by Li, J. J. Search for Related Content PubMed PubMed Citation Articles by Haaf, H. Articles by Li, J. J.

Influence of -Naphthoflavone on the Metabolism and Binding of Ethinylestradiol in Male Syrian Hamster Liver Microsomes: Possible Role in Hepatocarcinogenesis¹

Hormonal Carcinogenesis Laboratory, VA Medical Center, and Department of Urologic Surgery, University of Minnesota Medical School, Minneapolis, Minnesota 55417 [H. H., J. J. L.], and Institute for Toxicology, University of Würzburg, Würzburg, Federal Republic of Germany [M. M.]

The influence of -naphthoflavone (ANF) on the metabolism and binding of radiolabeled ethinylestradiol (EE₂) has been examined both in vitro and in vivo in hamster liver microsomes. [¹⁴C]EE₂ was metabolized extensively to seven major oxidative metabolites, 7-hydroxyEE₂, 4-hydroxyEE₂, 2-hydroxyEE₂, D-homoestrone, monohydroxyEE₂, and two dihydroxyEE₂ metabolites identified as catechols with the additional hydroxy group on ring B or C, and a nonpolar fraction. The main EE₂ metabolite found was 2-hydroxyEE₂, and it represented 47% of the total metabolites formed. The total amount of EE₂ catechol metabolites formed in untreated hamster liver microsomes was 65.6%. When ANF was added in vitro to these hepatic microsomes, there was a 27–45% decline in 2-hydroxyEE₂ formation, a 98% reduction in dihydroxyEE₂ (catechol-2), and a 56–66% reduction in the nonpolar fraction. The marked inhibition of EE₂ metabolism by the in vitro addition of ANF is reflected by a corresponding decrease in the irreversible binding of radioactive hormone to hamster liver microsomal proteins. In contrast, a biphasic response of ANF on EE₂ metabolism was observed after in vivo administration for 2.0 and 4.0 months. After 2.0 months of ANF treatment, there was a modest decline in all [¹⁴C]EE₂ metabolites, except 2-hydroxyEE₂ and dihydroxyEE₂ (catechol 1). After 4.0 months of ANF treatment, the reduction in EE₂ metabolism was even lower than after 2.0 months of treatment. Most interestingly, there was a 1.5-fold increase in 2-hydroxyEE₂ after 4.0 months of ANF treatment, representing nearly 69% of the total EE₂ metabolites formed. These results are consistent with an increase in irreversible binding of [¹⁴C]EE₂ metabolites to hamster liver microsomal proteins after 4.0 months of ANF treatment. The relative 1.3-fold and the absolute 1.5-fold increases in 2-hydroxyEE₂ after 2.0 and 4.0 months of ANF treatment in vivo, respectively, suggest that the elevation in this reactive EE₂ metabolite precursor may contribute importantly to hepatotumorigenesis in the hamster following prolonged EE₂ plus ANF treatment.

¹ This work was supported by Grants CA 41387 and CA 22008 from the National Cancer Institute, NIH, Department of Health and Human Services, and a grant from the General Medical Research Fund of the Veterans Administration.

² To whom requests for reprints should be addressed, at Hormonal Carcinogenesis Laboratory, VA Medical Center, 54th Street and 48th Ave., South, Minneapolis, MN 55417.

Received 2/29/88. Revised 6/24/88. Accepted 7/ 6/88.