title: Differential inhibition of human CYP3A4 and Candida albicans CYP51 with azole antifungal agents.
abstract: The inhibition by azole antifungals of human cytochrome CYP3A4, the major form of drug metabolising enzyme within the liver, was compared with their inhibitory activity against their target enzyme, Candida albicans sterol 14alpha-demethylase (CYP51), following heterologous expression in Saccharomyces cerevisiae. IC(50) values for ketoconazole and itraconazole CYP3A4 inhibition were 0.25 and 0. 2 microM. These values compared with much lower doses required for the complete inhibition of C. albicans CYP51, where IC(50) values of 0.008 and 0.0076 microM were observed for ketoconazole and itraconazole, respectively. Additionally, stereoselective inhibition of CYP3A4 and CYP51 was observed with enantiomers of the azole antifungal compounds diclobutrazol and SCH39304. In both instances, the RR(+) configuration at their asymmetric carbon centres was most active. Interestingly, the SS(-) enantiomeric form of SCH39304 was inactive and failed to bind CYP3A4, as demonstrable by Type II binding spectra.
authors.affiliation: Institute of Biological Sciences, University of Wales Aberystwyth, Aberystwyth, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Lamb
authors.forename: D E
authors.initials: DE
authors.lastname: Kelly
authors.forename: B C
authors.initials: BC
authors.lastname: Baldwin
authors.forename: S L
authors.initials: SL
authors.lastname: Kelly
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013045:Species Specificity; D058886:Sterol 14-Demethylase; D013379:Substrate Specificity
chemical_list: D000935:Antifungal Agents; D001393:Azoles; C548418:CYP51A1 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D058886:Sterol 14-Demethylase; C510163:CYP3A4 protein, human