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Pathway-Targeted Pharmacogenomics of CYP1A2 in Human Liver

Created: 27th Jan 2011 at 14:52
Last updated: 24th Oct 2013 at 16:20

Abstract:

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.