Relationships between non-occupational cadmium exposure and expression of nine cytochrome P450 forms in human liver and kidney cortex samples

This study was undertaken to assess associations between age, gender, cigar ette smoke and non-workplace cadmium exposure, and liver pathology and inte r-individual variation in cytochrome P450 (CYP) expression in human tissues . Autopsy specimens of twenty-eight Queensland residents whose ages ranged from 3 to 89 years were analyzed for the presence of nine CYP protein isofo rms by immunoblotting. All subjects were Caucasians and their liver cadmium contents ranged from 0.11 to 3.95 kg/g wet weight, while their kidney cadm ium contents were in the range of 2 to 63 mug/g wet weight. CYP1A2, CYP2A6, CYP2D6, CYP3A4, and CYP3A5 were detected in liver but not in kidney, and C YP1A1 and CYP1B1 were not found in liver or kidney. Lowered liver CYP2C8/19 protein contents were found to be associated with liver pathology. Importa ntly, we show elevated levels of CYP2C9 protein to be associated with cadmi um accumulation in liver. No mechanism that explains this association is ap parent, but there are two possibilities that require further study. One is that variation in CYP2C9 protein levels may be, in part, attributed to an i ndividual's non-workplace exposure to cadmium, or an individual's CYP2C9 ge notype may be a risk factor for cadmium accumulation. A positive correlatio n was found between liver CYP3A4 protein and subject age. Levels of liver C YPIA2 protein, but not other CYP forms, were increased in people more expos ed to cigarette smoke, but there was no association between CYPIA2 protein and cadmium. CYP2A6 protein was found in all liver samples and CYP2A6 gene typing indicated the absence of CYP2A6 null allele (CYP2A6(D)) in this samp le group, confirming very low prevalence of homozygous CYP2A6(D) in Caucasi ans. CYP2A6 gene types W/W, WIC, and CIC were not associated with variation s in liver microsomal CYP2A6 protein. CYP2D6 protein was absent in all twen ty-five kidney samples tested but was detectable in liver samples of all bu t two subjects, indicating the prevalence of the CYP2D6 null allele (CYP2D6 (D)) in this sample group to be about 7%, typical of Caucasian populations. (C) 2001 Elsevier Science Inc. All rights reserved.