ACETYLATION PHENOTYPE AND CYTOCHROME-P450IA2 PHENOTYPE ARE UNLIKELY TO BE ASSOCIATED WITH PERIPHERAL ARTERIAL-DISEASE

The hypothesis that cytochrome P450IA2 (CYPIA2) and/or N-acetyltransfe rase 2 (NAT2) may be involved in the pathogenesis of peripheral arteri al disease was investigated in 90 Australian patients with significant disease and 81 matched control subjects. CYPLA2 and NAT2 phenotypes w ere determined from urinary metabolite patterns after an oral dose of caffeine. NAT2 phenotype was similar (chi2 = 0.01; p = 0.98) in both a therosclerotic patients (43.3% rapid) and control subjects (42.0% rapi d). CYPIA2 metabolism as measured by the median ratio of (1,7-dimethyl xanthine + 1,7-dimethyluric acid)/caffeine was significantly induced b y smoking in both patients with atherosclerosis (ratio of 6.5 in nonsm okers and 12.4 in smokers; p < 0.05) and control subjects (ratio of 8. 2 in nonsmokers and 14.8 in smokers; p < 0.05), but values in atherosc lerotic and control nonsmokers and smokers were similar. Probit transf ormation of the data revealed a trimodal distribution of ratios in con trol subjects who were nonsmokers, with 5% classified as poor metaboli zers (homozygous rapid) and 95% as extensive metabolizers. The distrib ution of ratios in control subjects who were smokers was unimodal, whe reas among the patients with arterial disease, both smokers and nonsmo kers exhibited a bimodal pattern with 8.2% to 16% poor metabolizer and 84% to 91.8% extensive metabolizer phenotypes. When data from both no nsmokers and smokers were combined, the overall proportion of subjects who were poor metabolizers was not significantly different (chi2 = 1. 82; p = 0.18) between control subjects (3.8%) and patients with athero sclerosis (10.6%). Thus biotransformation of environmental or dietary aromatic or heterocyclic amines by NAT2 or CYPIA2 is unlikely to have a significant role in the cause or pathogenesis of peripheral arterial disease.