Involvement of cytochrome P450 and the flavin-containing monooxygenase(s) in the sulphoxidation of simple sulphides in human liver microsomes.
This study was conducted to examine the involvement of cytochrome P450 (CYP450) and the flavin-containing monooxygenase (FMO) in the sulphoxidation of ethyl methyl sulphide (EMS), 4-chlorophenyl methyl sulphide (CPMS) and diphenyl sulphide (DPS) in human liver microsomes from a phenotypic CYP2D6 extensive metabolizer. Human liver microsomes catalyzed the sulphoxidation of EMS, CPMS and DPS to their corresponding sulphoxides. Lineweaver-Burk plots for the sulphoxidation of EMS in human liver microsomes indicated that the apparent K(m) and V(max) were 1.53 +/- 0.07 mM and 1.11 +/- 0.25 nmoles/mg protein/min, respectively. The apparent K(m) and V(max) for the sulphoxidation of CPMS were 0.17 +/- 0.05 mM and 1.41 +/- 0.16 nmoles/mg protein/min, respectively. The apparent K(m) and V(max) for the sulphoxidation of DPS were 0.10 +/- 0.01 mM and 1.08 +/- 0.05 nmoles/mg protein/min, respectively. Methimazole noncompetitively inhibited the sulphoxidation of EMS, CPMS and DPS by human liver microsomes with K(i) values of 8.6 +/- 0.6, 5.7 +/- 0.4 and 6.6 +/- 0.5 mM, respectively. SKF525A noncompetitively inhibited the sulphoxidation of CPMS and DPS by human liver microsomes with K(i) values of 6.6 +/- 0.4 and 0.40 +/- 0.1 mM, respectively. The results suggest that FMO is involved in the sulphoxidation of EMS, CPMS and DPS while CYP450 is involved in the sulphoxidation of CPMS and DPS in human liver microsomes.
Nnane
Ivo P
IP
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19104, USA. ivo.nanne@temple.edu
Damani
Lyaquat A
LA
D002722:Chlorobenzenes / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008713:Methimazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010641:Phenotype; D011335:Proadifen / Q000494:pharmacology; D013440:Sulfides / Q000378:metabolism*
D002722:Chlorobenzenes; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D013440:Sulfides; C403226:ethylmethyl sulfide; C037534:4-chlorophenyl methyl sulfide; D008713:Methimazole; D011335:Proadifen; C444009:diphenyl sulfide; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D019389:Cytochrome P-450 CYP2D6