Cytochrome P4501A1 gene polymorphism and inducibility

Abstract

The inducibility of the enzyme CYP1A1 was examined in a cultured human lung explant system. An objective was to optimize and validate this model system for use in studies of the relationship between genotype and inducibility of CYP1A1. The enzyme was induced by the prototypic CYP1A1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and by the major tobacco smoke constituent, pyridine. The induction was observed at the level of mRNA (by RT-PCR analysis), protein (by western blot analysis), and activity (by the formation of DNA-binding derivatives from added benzo[a]pyrene (B[a]P)). In most cases, mRNA upregulation was more pronounced than protein induction. Pyridine was a better inducer than TCDD in some lung samples, whereas TCDD was a better inducer than pyridine in others. Mutant variants of the CYP1A1 gene were detected in some of the lung samples. The results show that the explant culture system is a suitable model for examining the inducibility of human pulmonary CYP1A1, and that pyridine and TCDD may both induce human pulmonary CYP1A1, but by different mechanisms. The results also show that mutant alleles of the CYP1A1 gene are present in a local population sample.