Current Drug Targets - Immune, Endocrine & Metabolic Disorders, 2005, 5, 439-448 439 1568-0088/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd. Hormonal Effects on Drug Metabolism Through the CYP System: Perspectives on Their Potential Significance in the Era of Pharmacogenomics N. J. Sarlis* ,1 and L. Gourgiotis 1 The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA and 2 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland 20892- 1758, USA 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. Key Words: Cytochrome, drug metabolism, endocrine, thyroid, glucocorticoid, pregnancy, diabetes, obesity, inflammation. I. INTRODUCTION The spectrum of physiologic and clinical responses of human subjects to a specific drug is called pharmacodynamics. These responses show considerable variation, depending on many factors, the bases of which are: a) non-genetic (age, tobacco use status, concomitant illnesses, nutrition, coadmin- istered drugs, and exposure to environmental pollutants and other xenobiotics in general), b) genetic (gender and the expression and activity of enzymes, drug transporters, and drug targets), and c) mixed (weight, body fat percentage, and liver/kidney/cardiovascular/respiratory function of the individual). A complex interplay among the above factors, the drug itself, and the host effector systems responsible for the action of the drug will ultimately determine the response to the drug in individual subjects [1]. This is in contradistinction to the study of pharmacodynamics in patient populations , in which more predictable data can emerge about the actions of specific drugs, mainly due to the phenomenon of statistical averaging. Therefore, although the knowledge basis of using drugs for disease treatment (pharmacology) is based on population-derived studies, the significance of our exact knowledge (or at least predictive ability) of the effect of any drug on an individual patient in clinical practice cannot be overemphasized. *Address correspondence to this author at the Associate Professor of Medicine, The University of Texas M. D. Anderson Cancer Center, Department of Endocrine Neoplasia and Hormonal Disorders, 1515 Holcombe Blvd., Unit 435, Houston, TX 77030-4009, USA; Tel: 713-792- 2841; Fax: 713-794-4065; E-mail: njsarlis@mdanderson.org Drug metabolism is carried out in two phases: Phase I involves the oxidation, reduction, hydrolysis, or other transformation of a given drug molecule; these chemical reactions occur mainly through the action of enzymes belonging to the cytochrome p450 (CYP) family. In phase II, the solubility of the drug is increased by glycuronidation, sulfation, acetylation, or methylation, thus, enhancing its elimination. In this review, we summarize the existing data on the complex association between hormones and the CYP system. We shall use the term “hormones” broadly, including mediator molecules secreted by immune/inflammatory cells (i.e. cytokines and interleukins) and moieties that are not classically or universally considered as part of the endocrine/ hormonal system but still exert systemic actions (e.g., prostaglandins, histamine, serotonin, and adrenergic agonists). Most studies are based on in vitro experiments or tissue- or whole animal-based experiments. Human studies in this field are scarce and generally involve a small number of patients. As a rule, modulation of the CYP system is selective for each enzyme class or subclass (as described in section III). Consequently, results have not been consistent among the existing studies. This is a novel and emerging field of study that currently contains large swaths of unexplored territory. We believe that our contribution is timely, as further study of the effect of changes in the activity of endocrine systems on CYP enzymes may explain—at least in part—unexpected, idiosyncratic, diminished, or exaggerated drug actions observed in a variety of disease states. Classification of these