Specific and enantioselective sulfoxidation of an aryl-trifluoromethyl sulfide by rat liver cytochromes P-450.
Evidence based on thermal stability and enzyme inhibition data suggests that the sulfoxidation of the drug toltrazuril by rat liver microsomes is catalyzed by different cytochromes P-450. Pretreatment of rats by different inducers--phenobarbital, 3-methylcholanthrene, dexamethasone, and triacetyloleandomycin--results in a 2.1-, 2.6-, 2.9-, and 1.8-fold increase, respectively, in the rate of sulfoxidation. The highest increase (8.4-fold) was observed after treatment of microsomes from triacetyloleandomycin-treated animals by potassium ferricyanide. Castration and aging also modify the sulfoxidase activity. The relative rate of formation of the two toltrazuril enantiomers [(A)- and (B)-sulfoxides] depends on the source of the microsomes, suggesting that different cytochromes P-450 have different stereoselectivities.
Unité de Toxicologie Métabolique et d'Ecotoxicologie INRA-ENVL, Ecole Nationale Vétérinaire de Lyon, Marcy l'Etoile, France.
E
E
Benoit
T
T
Cresteil
J L
JL
Riviere
P
P
Delatour
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D013237:Stereoisomerism; D013454:Sulfoxides / Q000378:metabolism*; D014227:Triazines / Q000493:pharmacokinetics*
D007527:Isoenzymes; D013454:Sulfoxides; D014227:Triazines; D003577:Cytochrome P-450 Enzyme System; C036670:toltrazuril