Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol.
Previous studies of propofol (2,6-diisopropylphenol) pharmacology have shown that this widely used anaesthetic drug is extensively cleared from the body by conjugation of the parent molecule or its quinol metabolite. On the basis of potential influence of propofol on the metabolism of co-administered agents, many investigators have evaluated the effects of propofol on cytochrome P450 (CYP) activities. CYP isoforms involved in propofol metabolism are not defined. In this study, our objective was to elucidate further the CYP isoforms responsible for the hydroxylation of propofol. Using microsomes from 12 different human livers, we investigated CYP isoforms involved in propofol hydroxylase activity, using selective chemical inhibitors of CYP isoforms, correlation with immunoquantified specific CYP isoform content, immunoinhibition, and 11 functionally active human CYP isoforms expressed in a heterologous system (yeast and human B-lymphoblastoid cells). We found a low variability in the production of the hydroxylated metabolite of propofol, 2,6-diisopropyl-1,4-quinol. This activity was mediated by CYP and followed Michaelis-Menten kinetics with apparent K(M) and Vmax values of 18 microM (95% Cl 15.1-20.1) and 2.6 nmol min-1 mg-1 (95% Cl 2.45-2.68) respectively. Part of the propofol hydroxylase activity was mediated by CYP2C9 in human liver, especially at low substrate concentration. Moreover, propofol was likely to be metabolized by additional isoforms such as CYP2A6, 2C8, 2C18, 2C19 and 1A2, especially when substrate concentrations are high. This low specificity among CYP isoforms may contribute to the low interindividual variability (two-fold) and may contribute to the low level of metabolic drug interactions observed with propofol.
Université Claude Bernard, Lyon, France.
J
J
Guitton
T
T
Buronfosse
M
M
Desage
J P
JP
Flinois
J P
JP
Perdrix
J L
JL
Brazier
P
P
Beaune
D018686:Anesthetics, Intravenous / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D015742:Propofol / Q000378:metabolism*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000502:physiology
D018686:Anesthetics, Intravenous; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D015742:Propofol