Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: Role of CYP2C isoforms in human liver microsomes

The involvement of cytochromes P450 (CYPs) in the oxidation of ethanol into acetaldehyde was investigated by using 16 recombinant human CYP isoforms. Apparent Km and Vm were determined for CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP3A4 and CYP4A11. All of the tested CYPs, except CYP2A6 and CYP2C18, metabolized ethanol into significant amounts of acetaldehyde and displayed Km values around 10 mM. The significant correlation found between ethanol oxidation and CYP2E1, CYP3A4 and CYP1A2 catalytic activities in a panel of human liver microsomes confirmed the strong implication of these CYPs in ethanol metabolism. The contribution of CYP2C isoforms which are the most abundant in the liver after CYP3A4, was studied using selective inhibitors either with recombinant CYP2C isoforms or in human liver microsomes. Tienilic acid (100 μM) and ticlopidine (20 μM), mechanism-based inhibitors of CYP2C9 and CYP2C19, respectively, decreased ethanol oxidation by 8 ± 1.2% and 7.6 ± 1.6% in human liver microsomal samples while selective inhibitors of CYP2E1 (DEDTC 100 μM), CYP3A4 (TAO 50 μM) and CYP1A2 (furafylline 25 μM) decreased it by 11.9 ± 2.1%, 19.8 ± 1.9% and 16.3 ± 3.9%, respectively. As ethanol can be metabolized by most of CYPs, it helps to explain or predict alcohol–xenobiotics interactions which are of high importance in medical prescription.