Enantioselective S-oxygenation of para-methoxyphenyl-1,3-dithiolane by various tissue preparations: effect of estradiol

• Published in: Molecular pharmacology Vol. 37; no. 2; pp. 319 - 327
• Main Authors: CASHMAN, J. R, OLSEN, L. D, LAMBERT, C. E, PRESAS, M. J
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.02.1990
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Cytochrome P-450 Enzyme System - metabolism; Enzymes and enzyme inhibitors; estradiol; Estradiol - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Heterocyclic Compounds - metabolism; Kidney - enzymology; Lung - enzymology; Microsomes - drug effects; Microsomes - enzymology; Microsomes, Liver - enzymology; Ovariectomy; Oxidation-Reduction - drug effects; Oxidoreductases; Oxygenases - metabolism; Rats; Rats, Inbred Strains; Stereoisomerism; Substrate Specificity; Hemoprotein; Enantioselectivity; Rat; Enzyme; Cytochrome P450; Rodentia; Estrogen; HPLC chromatography; 17β-Estradiol; NMR spectrometry; Microsome; Diastereoselectivity; Ovarian hormone; Oxygenase; Vertebrata; Mammalia; Enzymatic activity; Flavoprotein-linked monooxygenase; Female; Sex steroid hormone; Oxygenation
• ISSN: 0026-895X; 1521-0111

Liver, kidney, and lung microsomes prepared from nonpretreated female Sprague-Dawley rats catalyze the NADPH- and oxygen-dependent S-oxygenation of para-methoxyphenyl-1,3-dithiolane. Studies on the biochemical mechanism of dithiolane S-oxygenation in liver, kidney, and lung microsomes suggest that this reaction is catalyzed in a diastereoselective and enantioselective fashion by the flavin-containing monooxygenase and, to a lesser extent, the cytochromes P-450. This conclusion is based on results examining the effects of selective cytochrome P-450 inhibitors and positive effectors, microsome heat-inactivation treatment, and alternate substrates for the flavin-containing monooxygenase. Liver and kidney microsomes prepared from ovarectomized female rats tended to have decreased S-oxygenase activity, compared with nonpretreated female rats, whereas ovarectomized rats pretreated with estradiol had markedly lower S-oxygenase activity. In contrast, lung microsomal S-oxygenase activity, which is low in pulmonary microsomes from nonpretreated female rats, increases 2-4-fold after ovariectomization and estradiol pretreatment. In female Sprague-Dawley rats, estradiol pretreatment is mainly responsible for the large decrease (or increase) in S-oxygenase activity observed in the tissues examined, although it is unlikely that estradiol alone controls flavin-containing monooxygenase S-oxygenase activity.