Expression of cytochrome P4502E1 in human liver: assessment by mRNA, genotype and phenotype.
Cytochrome P4502E1 (CYP2E1) is constitutively expressed in human liver and is responsible for the metabolic bioactivation of a wide variety of xenobiotics, including a number of protoxins and procarcinogens. CYP2E1 expression is regulated at several levels including pre-transcriptional, transcriptional and post-transcriptional levels, and any variation in enzyme concentration and hence activity may represent increased risk of toxicity or carcinogenicity. We have investigated variability in the levels of CYP2E1 mRNA, protein and functional activity in a human liver bank, and attempted to relate these parameters to the RsaI restriction fragment length polymorphism in the 5'-flanking region. Variation in CYP2E1 mRNA (18-fold) was greater than the variation seen in CYP2E1 protein (twofold) and functional activity (fourfold) determined using two probe substrates, chlorzoxazone and p-nitrophenol. Although protein and functional activity showed a significant correlation (r = 0.93 and r = 0.83 for chlorzoxazone and p-nitrophenol, respectively), there was no correlation between any of these parameters and mRNA levels. Also, the variation in CYP2E1 activity could not be directly accounted for by the RsaI polymorphism in our samples. In conclusion, our results are consistent with a complex regulation of CYP2E1 and the fact that it is highly conserved in the human population. The absence of a relationship between the RsaI polymorphism and CYP2E1 activity is consistent with other studies performed in Caucasians, but does not exclude an effect of this polymorphism on inducibility of CYP2E1.
Powell
H
H
Department of Pharmacology and Therapeutics, The University of Liverpool, UK.
Kitteringham
N R
NR
Pirmohamed
M
M
Smith
D A
DA
Park
B K
BK
D000328:Adult; D000368:Aged; D002753:Chlorzoxazone / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D009596:Nitrophenols / Q000378:metabolism; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D012333:RNA, Messenger / Q000032:analysis; D014019:Tissue Donors
D009596:Nitrophenols; D012333:RNA, Messenger; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone; C024836:4-nitrophenol