The genotypic basis of interindividual variation in levels of induced CYP1A1 activity has been investigated by screening both theCYP1A1gene and theAhreceptor gene (AhR) for both previously described and novel polymorphisms. A 103-fold level of interindividual variation in induced CYP1A1 activity [ethoxyresorufinO-deethylase (EROD)] was observed in lymphocytes from a group of 30 Caucasian volunteers. High levels of induced EROD activity did not correlate with the presence ofCYP1A1*2orCYP1A1*4alleles or with theGSTM1null genotype. NovelCYP1A1alleles with the base substitutions C4151T, G-469A and C-459T respectively, were detected by screening the coding exons and approximately 1 kb of upstream sequence in 20 individuals by single-strand conformational polymorphism (SSCP) analysis but none of the three novel alleles appeared to be associated with high induced CYP1A1 activity in the study group. Screening of the 11 exons of theAhRgene by SSCP analysis confirmed the existence of the previously describedG1721Apolymorphism in a Caucasian population and a novel allele (G1768A which results in the amino acid substitution V5701) was also detected. The novel allele was very rare in Caucasians though more common in African-Americans. Individuals with at least one copy of the G1721AAhRvariant allele showed a significantly higher level of induced CYP1A1 activity compared with individuals negative for the polymorphism (P = 0.0001). A similar finding was obtained for induced CYP1A1 protein levels determined by immunoblotting. Levels of induced CYP1A1 activity were also found to show a sex difference with women showing a significantly lower induced activity compared with men. We conclude that genotypes for the G1721AAhRpolymorphism and gender appear to be determinants of levels of induced CYP1A1 activity and that interindividual variation in levels of induced CYP1A1 activity appears to be associated more with regulatory factors than polymorphism in theCYP1A1gene.