The human
drug metabolizing
cytochrome P450 (
CYP) 1A2, is one of the major P450
isoforms contributing by about 5-20% to the hepatic P450 pool and catalyzing oxidative biotransformation of up to 10% of clinically relevant drugs including
clozapine and
caffeine.
CYP1A2 activity is interindividually highly variable and although twin studies have suggested a high heritability, underlying genetic factors are still unknown. Here we adopted a pathway-oriented approach using a large human liver bank (n = 150) to elucidate whether variants in candidate genes of constitutive,
ligand-inducible, and pathophysiological inhibitory regulatory pathways may explain different hepatic
CYP1A2 phenotypes. Samples were phenotyped for
phenacetin O-deethylase activity, and the expression of
CYP1A2 protein and
mRNA was determined.
CYP1A2 expression and function was increased in smokers and decreased in patients with
inflammation and
cholestasis. Of 169 SNPs in 17 candidate genes including the CYP1A locus, 136 non-redundant SNPs with minor allele frequency >5% were analyzed by univariate and multivariate methods. A total of 13 strong significant associations were identified, of which 10 SNPs in the ARNT, AhRR, HNF1α, IL1β, SRC-1, and VDR genes showed consistent changes for at least two phenotypes by univariate analysis. Multivariate linear modeling indicated that the polymorphisms and non-genetic factors together explained 42, 38, and 33% of
CYP1A2 variation at activity,
protein and
mRNA levels, respectively. In conclusion, we identified novel trans-associations between regulatory genes and hepatic
CYP1A2 function and expression, but additional genetic factors must be assumed to explain the full extent of
CYP1A2 heritability.