title: CYP3A4-mediated oxidation of lisofylline to lisofylline 4,5-diol in human liver microsomes.
abstract: The cytochrome P450s responsible for the conversion of lisofylline, a drug being developed to prevent the complications of high-dose chemotherapy, to lisofylline 4,5-diol, one of two principal metabolites in human liver microsomes, were evaluated. Lisofylline diol formation in microsomes prepared from five adult human livers was biphasic, with respective Km values of 0.0230+/-0.015 and 4.23+/-2.8 mM (mean +/- SD) and respective Vmax values of 0.0565+/-0.052 and 0.429+/-0.15 nmol/min/mg of protein. Through studies with isoform selective chemical inhibitors, CYP3A4 was implicated as the low Km enzyme from 89.0+/-11.2% inhibition of lisofylline 4,5-diol formation by troleandomycin at 50 microM substrate and CYP2A6 was implicated as the high Km enzyme. The formation of lisofylline 4,5-diol by these enzymes was confirmed with cDNA-expressed human CYP3A4 and CYP2A6.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle 98195, USA.
authors.forename: H S
authors.initials: HS
authors.lastname: Shin
authors.forename: J T
authors.initials: JT
authors.lastname: Slattery
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C111875:lisofylline 4,5-diol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C025189:lisofylline; D010431:Pentoxifylline