P 450 cytochromes are responsible for the metabolism of a wide variety of environmental carcinogens, such as tobacco smoke, and also endogenous hormones. The oxidative metabolism of estradiol follows two mutually exclusive pathways, 2 and 16 hydroxylation, with opposite biological properties. The 2-hydroxylated (C-2) metabolites are devoid of peripheral biological activity, while the 16-hydroxyalted (C-16) metabolites are estrogen agonists.

We study polymorphisms in the CYP1A1 gene, which may influence the degree of estrogen C-2 hydroxylation and, consequentially, individual susceptibility to breast cancer. Polymorphisms of the gene also affect tobacco metabolism, possibly increasing the risk of lung cancer. Three CYP1A1 gene polymorphisms have been described, two of which (exon 7 and AA) have functional activity. We observed racial/ethnic differences in the prevalence of the three polymorphisms; the AA polymorphism is only present in African-American subjects and has never been observed in Caucasians or Asian. We just completed two case-control studies in African-Americans, on breast and lung cancer, respectively, to assess whether subjects carrying certain CYPA1A polymorphisms are at increased risk for the two types of cancer.

Furthermore, we are conducting a chemopreventive studying using indole-3-carbinol, a compound derived from vegetables and a potent inducer of C-2 estradiol hydroxylation, to test whether this compound will modify CYPA1A activity and estrogen metabolism differently in women with different CYPA1A polymorphisms. Our goal, in terms of public health, is to identify individuals who may be at increased risk for cancer and to develop chemopreventive strategies.