title: Inhibition of cytochrome P450 2E1 by propofol in human and porcine liver microsomes.
abstract: While almost anesthetics are metabolized by the cytochrome P450 (CYP) 3A4, some major volatile ones such as halothane and sevoflurane are metabolized by CYP2E1 in humans. To determine whether 2,6-diisopropylphenol (propofol), a widely used intravenous anesthetic agent, known to inhibit CYP3A4 and CYP1A2, also inhibits CYP2E1, 6-OH hydroxylation of chlorzoxazone, a prototypical CYP2E1 substrate, was estimated using two pools of human microsomes and one pool of porcine microsomes from seven livers. Basal human enzyme activities were characterized by a V(max) of 1426+/-230 and 288+/-29 pmol min(-1)mg(-1) protein and a K(m) of 122+/-47 and 149+/-42 microM, while the corresponding porcine activities were associated with a V(max) of 352+/-42 pmol min(-1)mg(-1) protein and a K(m) of 167+/-38 microM. A competitive inhibition of CYP2E1 by propofol was observed with low inhibition constants in the therapeutic range in both porcine (19 microM) and human (48 microM) liver microsomes. These in vitro results suggest that propofol could have a protective effect on toxic metabolite activation of compounds catalyzed by CYP2E1.
authors.affiliation: INSERM U456, Faculté de Pharmacie, Université de Rennes 1, Room 2, avenue du Prof. Léon Bernard, 35043 Rennes cedex, France. corinne.lejus@chu-nantes.fr
authors.forename: Corinne
authors.initials: C
authors.lastname: Lejus
authors.forename: Alain
authors.initials: A
authors.lastname: Fautrel
authors.forename: Yannick
authors.initials: Y
authors.lastname: Mallédant
authors.forename: André
authors.initials: A
authors.lastname: Guillouzo
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D015742:Propofol / Q000494:pharmacology*; D013552:Swine
chemical_list: D018686:Anesthetics, Intravenous; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D015742:Propofol