Human cytochrome P450 2E1 (CYP2E1): from genotype to phenotype.
CYP2E1 is involved in the activation of various carcinogens, including N-nitrosamines, which are believed to be important in human carcinogenesis. Humans exhibit wide interindividual variability in levels of CYP2E1 mRNA and protein, which might explain interindividual differences in susceptibility to carcinogens activated by CYP2E1. Such variability could be due either to genetic polymorphisms observed in the CYP2E1 gene (Rsa I in the 5'-flanking region, Dra I in intron 6 and Taq I in intron 7) or to varying inducibility by xenobiotics. The aim of the present study was to establish whether, in a Caucasian population (n = 93), there existed a relationship between allelic forms of the CYP2E1 gene and the phenotype determined in vitro by hepatic ability to 6-hydroxylate chlorzoxazone. Rates of chlorzoxazone-6-hydroxylation were significantly correlated with levels of immunochemically measured CYP2E1 (p < 0.001). CYP1A2, 2C8, 2C9, 2C18, 2D6, 3A4 and 3A5 did not appear to be significantly involved in chlorzoxazone metabolism, whereas the participation of CYP1A1 could not be excluded. Frequencies of the rare alleles for the three polymorphism sites were 2.2% for RsaI, 7.5% for DraI and 8.5% for TaqI. Despite substantial interindividual variations in chlorzoxazone hydroxylase activity, no relationship between any of the three polymorphisms and CYP2E1 activity was established. Therefore, in humans, interindividual variability in CYP2E1 levels is probably due to differing induction levels as a result of environmental factors, or to genetic factors other than those studied in this work.
Carrière
V
V
INSERM U75, CHU-Necker, Université René Descartes, Paris, France.
Berthou
F
F
Baird
S
S
Belloc
C
C
Beaune
P
P
de Waziers
I
I
D000483:Alleles; D002753:Chlorzoxazone / Q000031:analogs & derivatives / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D010641:Phenotype
C039289:6-hydroxychlorzoxazone; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone