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Guengerich FP. Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene. Chem Res Toxicol. 1990;3(4):363-71doi: 10.1021/tx00016a015.
Guengerich, F. P. (1990). Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene. Chemical research in toxicology, 3(4), 363-71. https://doi.org/10.1021/tx00016a015
Guengerich, F P. "Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene." Chemical research in toxicology vol. 3,4 (1990): 363-71. doi: https://doi.org/10.1021/tx00016a015
Guengerich FP. Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene. Chem Res Toxicol. 1990 Jul-Aug;3(4):363-71. doi: 10.1021/tx00016a015. PMID: 2133086.
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Chem Res Toxicol. 1990 Jul-Aug;3(4):363-71. doi: 10.1021/tx00016a015.

Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene.

Chemical research in toxicology

F P Guengerich

Affiliations

  1. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.

PMID: 2133086 DOI: 10.1021/tx00016a015

Abstract

A series of 17 alpha-acetylenic steroids was examined with regard to ability to inactivate human liver microsomal cytochrome P-450 (P-450) IIA4, an enzyme involved in the oxidation of a number of drugs, carcinogens, and steroids, including estrogens and progestogens. Of the eight compounds tested, gestodene was found to be particularly active as a mechanism-based inactivator of P-450 IIIA4. Inhibition of both microsomal nifedipine oxidation and 17 alpha-ethynylestradiol (EE) 2-hydroxylation was dependent upon NADPH and gestodene concentration. Rates of inactivation were pseudo first order-values of kinactivation = 0.4 min-1 and Ki = 46 microM and a partition ratio of 9 were calculated. The kinactivation is approximately 50-fold greater than estimated for EE and is one of the highest reported for P-450 mechanism-based inactivators. Spectrally detectable P-450 was also destroyed in microsomes, but several experiments indicate that little covalent binding to amino acid residues of P-450 IIIA4 occurs. Microsomal inactivation of P-450 could be blocked by the presence of other P-450 IIIA4 substrates, and several activities catalyzed by other P-450s were not inhibited under conditions in which greater than 90% of P-450 IIIA4 was inactivated. Consideration of structure/activity relationships among the 17 alpha-acetylenic steroids examined indicates that the delta 15 double bond is critical but is not in itself sufficient for the inactivation process, which is postulated to result from attack of P-450 on the substituted acetylenic carbon and lead to porphyrin N-alkylation. The effectiveness of this mechanism-based inactivator may account for reports of increased estrogen and steroid levels in some women using gestodene in oral contraceptives.

Keywords: Americas; Biology; Clinical Research; Contraception; Contraceptive Agents, Estrogen--pharmacodynamics; Contraceptive Agents, Female--pharmacodynamics; Contraceptive Agents, Progestin--pharmacodynamics; Contraceptive Agents--pharmacodynamics; Contraceptive Methods--pharmacodynamics; Developed Countries; Diseases; Drug Interactions; Drugs; Embolism; Enzyme Inhibitors; Enzymes And Enzyme Inhibitors; Ethinyl Estradiol--pharmacodynamics; Examinations And Diagnoses; Family Planning; Gestodene--pharmacodynamics; Hepatic Effects; In Vitro; Laboratory Examinations And Diagnoses; Laboratory Procedures; Methodological Studies; North America; Northern America; Oral Contraceptives, Combined--pharmacodynamics; Oral Contraceptives--pharmacodynamics; Physiology; Research Methodology; Tennessee; Thromboembolism; Thrombosis; Treatment; United States; Vascular Diseases

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