Hormonal effects on drug metabolism through the CYP system: perspectives on their potential significance in the era of pharmacogenomics.

ABSTRACT

Cytochrome P450 (CYP) is a group of enzymes that metabolize drugs to a more water-soluble form, rendering them available for renal excretion. The major site of CYP expression is the liver. Nearly 50% of all medications currently on the market are metabolized by the enzyme CYP3A4, while metabolism of another 35-40% occurs through enzymes CYP1A2, CYP2C19, CYP2D6, CYP3A5 CYP3A6, and CYP3A7. Here, we summarize the current knowledge of the effects of hormones on the CYP family. The term "hormone" is used in its broad sense and includes products of the major endocrine glands (i.e., thyroid, adrenals, gonads, pancreas) and compounds that are not classically considered hormones, such as neurogenic amines, cytokines, interleukins, and eicosanoids. In addition, we comment on the effects on CYP expression of states associated with profound hormonal changes, such as pregnancy, malnutrition, obesity, diabetes mellitus, systemic inflammation, and conditions of altered extracellular fluid volume or osmolality. Available data are limited and are derived primarily from in vitro and animal studies. Moreover, the picture is obscured by conflicting results among studies and the complexity of the regulation of the expression and activity of elements of the CYP system. While the clinical significance of hormonal effects on the CYP system remains to be determined, we anticipate that such effects will be most pertinent to drugs with a narrow therapeutic range. Further research is needed to determine the scope and significance of these effects in view of rapid advances in the field of pharmacogenomics and the ever-increasing number of drugs available for therapeutic use.