Search for an association between the human CYP1A2 genotype and CYP1A2 metabolic phenotype

Abstract

The genotype responsible for more than 60-fold interindividual differences in human hepatic CYP1A2 constitutive expression is not understood. Resequencing the human CYP1A1_CYP1A2 locus (39.6 kb) in five major geographically isolated subgroups recently led to the identification of 85 single nucleotide polymorphisms (SNPs), 57 of which were double-hit SNPs. Here, we attempted to correlate the CYP1A2 genotype with a metabolic phenotype. We chose 16 SNPs (all having a minor allele frequency > or =0.05 in Caucasians) to genotype 32 DNA samples (26 Caucasians, six Ethiopians) in which CYP1A2 metabolism had previously been determined. From 280 subjects (five locations worldwide) that had been CYP1A2-phenotyped, we genotyped the 10 highest, 14 lowest and eight intermediate DNA samples. Although no SNP was significant (P<0.05), possibly due to the small sample size, we found a trend for several of the six SNPs across the CYP1A2 linkage disequilibrium block associated with the trait. Five CYP1A2 haplotypes were inferred, two of which had not previously been reported; haplotype 1A2H10 showed the greatest association with CYP1A2 activity. Regulatory sequences responsible for the large interindividual differences in hepatic CYP1A2 gene basal expression might reside, in part, with some of these CYP1A2 SNPS but, in large part, might be located either cis (in nearby sequences not yet haplotyped) or trans in that they are not linked to the gene. We conclude that no SNP or haplotype in the CYP1A2 gene has yet been identified that can unequivocally be used to predict the metabolic phenotype in any individual patient.

HPLC determination of caffeine and paraxanthine in urine: An assay for cytochrome P450 1A2 activity

“…For some metabolic enzymes, this can be predicted by genotype; for others, such as P450 1A2, the genotype does not allow for prediction of phenotype [4]. Given the role of P450 1A2 in metabolism of several important pharmaceutical drugs and in activation of chemical carcinogens, there is great interest in methods to determine an individual's P450 1A2 phenotype.…”

“…However, prediction of metabolic phenotype based on genotype with P450 1A2 has proven to be challenging and is an area of research that generates continued controversy. Multiple studies have shown that genotype for P450 1A2 does not appear to result in a specific interindividual variation or phenotype of P450 1A2 metabolic activity [4,12,24]. In the end, interindividual differences in phenotypic P450 1A2 activity still remain of great interest because of the connection with drug metabolism and carcinogen metabolism.…”

“…Over 85 single nucleotide polymorphisms (SNPs) in the P450 1A2 gene locus have been identified [4]. Efforts to associate these genotypes with P4501A2 metabolic phenotypes have been ongoing.…”

“…The focus of this paper is to introduce instructors and students to an experimental investigation of P450 metabolism in humans, specifically metabolism of caffeine by P450 1A2. P450 1A2 is present in the liver primarily, but is inducible in the intestine, skin, lymphocytes, placenta, lung, gastrointestinal tract, pancreas, and brain [3,4]. Besides caffeine, P450 1A2 is involved in the metabolism of several pharmaceutical drugs as well as environmental carcinogens.…”

Functional characterization of eight human cytochrome P450 1A2 gene variants by recombinant protein expression

“…9 The spacer sequence may contain distinct regulatory regions of each gene or, alternatively, the regulatory regions of both genes. 10 CYP1A1 is mainly expressed in extrahepatic tissues, whereas CYP1A2 is almost exclusively expressed in the liver, representing B15% of its total CYP content. 11 CYP1A enzymes catalyze the bioactivation of pre-carcinogens, such as polycyclic aromatic hydrocarbons (CYP1A1), as well as aromatic and heterocyclic amines (CYP1A2).…”