CYP1A1 levels in lung tissue of tobacco smokers and polymorphisms of CYP1A1 and aromatic hydrocarbon receptor

Induction of a polycyclic aromatic hydrocarbon-metabolizing cytochrome P450 isoform CYP1A1 is regulated by aromatic hydrocarbon receptor (AHR). High i nducibility of CYP1A1, possibly due to genetic polymorphisms, has been cons idered to be a risk factor for lung cancer in tobacco smokers. The relation ship between low or high pulmonary expression of CYP1A1 and polymorphic gen otypes of CYP1A1 and AHR was investigated in 73 active smokers. CYP1A1 expr ession was determined in surgical lung samples by measuring ethoxyresorufin O-deethylase (EROD) activity and by immunostaining for CYP1A1 protein. The most common allelic variants of CYP1A1 and AHR in Finns, i.e. the MspI var iant (CYP1A1*2A), 1462V variant (CYP1A1*2B), and -459C to T variant of CYP1 A1 and the R554K variant (AHR*2) of AHR were studied using polymerase chain reaction based methods. EROD activity correlated positively with the daily cigarette consumption (r = 0.45). There was additional variation in EROD a ctivity independent of the amount of smoking e.g. among those who smoked on e pack per day until the day of operation, EROD activity ranged from 4-142 (median 48) pmol/min/mg. The frequencies of the MspI, 462V, and -459T varia nt alleles of CYP1A1 and 554K variant allele of AHR were 0.158, 0.055, 0.05 5 and 0.075, respectively. No differences were observed in the frequencies of polymorphic genotypes between the smokers with low and those with high e xpression, when the relationship was studied using a regression analysis ad justed for cigarette consumption. Our results thus indicate that the interi ndividual variation of CYP1A1 levels in smokers' lung tissue is not attribu table to genetic polymorphisms of CYP1A1 or AHR tested in this study. Pharm acogenetics 11: 501-509 (C) 2001 Lippincott Williams & Wilkins.