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Departments of Environmental Health and Toxicology [Z-Y. Z., M. J. F., L. S. K.] and Biomedical Sciences [L. H.], School of Public Health, University at Albany, State University of New York, and New York State Department of Health [L. S. K., M. J. F.], Albany, New York 12201, and Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 [F. P. G.]
Human cytochrome P4501A1 (CYP1A1) occurs extrahepatically and is polymorphic, the common form having Ile at position 462 and the rare form having Val. The rare allele has been associated with enhanced susceptibility to lung cancer. To resolve its role in cancer we have constructed CYP1A1-Val462 cDNA by site-directed mutagenesis from CYP1A1-Ile462, as confirmed by sequencing and allele-specific PCR. Both alleles were expressed in Escherichia coli, and CYP1A1-Ile462 and -Val462 were purified to electrophoretic homogeneity. The secondary structures of both forms were virtually identical, with high 
helix content, as assessed by circular dichroism. The P450s stereoselectively and regioselectively catalyzed the metabolism of (R)- and (S)-warfarin, in reconstituted systems, with very similar profiles. Both P450s produced (R)-6- and 8-hydroxy-warfarin with Km values of 0.40 ± 0.06 and 0.43 ± 0.05 mM, respectively, and Vmax values of 84.0 ± 6.8 and 137.7 ± 8.9 pmol/min/nmol CYP1A1-Val462, respectively, 1.0 ± 0.1 and 1.0 ± 0.1 mM, respectively, and 46.7 ± 2.5 and 80.0 ± 4.4 pmol/min/nmol CYP1A1-Ile462, respectively. Reconstituted CYP1A1-Val462 catalyzed ethoxyresorufin metabolism at a slightly but significantly higher rate than did CYP1A1-Ile462; Vmax values were 4.4 ± 0.6 and 3.1 ± 0.3 nmol/min/nmol CYP1A1, respectively. However, with the carcinogen benzo(a)pyrene as substrate, reconstituted CYP1A1-Ile462 together with epoxide hydrolase produced 7,8- and 9,10-dihydrodiols at comparable rates than did CYP1A1-Val462. Thus, the apparently greater susceptibility of the CYP1A1-Val462 genotype to lung cancer is probably not related to greater extents of carcinogen bioactivation.
1 This work was supported by NIH Grants ESO4238 (L. S. K.) and CA44353 and ESOO267 (F. P. G.).
2 To whom requests for reprints should be addressed, at New York State Department of Health, Wadsworth Center, P.O. Box 509, Albany, NY 12201.
Received 3/25/96. Accepted 6/28/96.
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