Enantioselective S-oxygenation of para-methoxyphenyl-1,3-dithiolane by various tissue preparations: effect of estradiol.
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.
Cashman
J R
JR
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446.
Olsen
L D
LD
Lambert
C E
CE
Presas
M J
MJ
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006571:Heterocyclic Compounds / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology; D010052:Ovariectomy; D010084:Oxidation-Reduction / Q000187:drug effects; D010105:Oxygenases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013379:Substrate Specificity
D006571:Heterocyclic Compounds; D004958:Estradiol; C063036:4-methoxyphenyl-1,3-dithiolane; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)