Effects of Polymorphisms of the CYP450 Enzyme Genes on Estrogen Status and the Risk for Osteoporosis

Several enzymes belonging to the CYP450 group are involved in the biosynthesis and metabolism of estrogen. Polymorphisms of the genes encoding for these enzymes have been linked to hormone-related diseases, notably breast cancer. These associations are based on the notion that certain variants of these enzymes have altered activity resulting in an alteration in estrogenic state, which in turn leads to differences in the risk for hormone-related disorders. Recent studies have indicated that these same polymorphisms are also important determinants of bone mineral density (BMD) and osteoporosis, another hormone-dependent condition. To name some, certain polymorphisms in the CYP19, CYP17, CYP1A1 and CYP1B1 genes have been found to affect BMD. So far, in this context, the most extensively investigated polymorphisms are those of the CYP19, the gene that codes for aromatase, an important enzyme in the estrogen biosynthetic pathway that converts androgenic steroids to estrogen. To our knowledge, four important polymorphisms of the aromatase gene are associated with differences in BMD and the risk for osteoporosis. Newer data further suggest that response to estrogen or hormone therapy may also be influenced by polymorphisms in the aromatase gene. And finally, a recent report indicates that polymorphisms of the genes encoding for the enzymes that metabolize estrogen are also important determinants of BMD. The C4887A polymorphism in the CYP1A1 gene is found to be associated with increased estrogen catabolism and lower femoral BMD in women carrying the A allele, present in 19% of the population. A similar (unpublished) observation is also noted for one of the CYP1B1 gene polymorphisms. The main focus of this review is to examine the effects of polymorphisms of the CYP 450 enzyme genes involved in estrogen biosynthesis and metabolism on BMD and the risk for osteoporosis.