Cytochrome P450 and Xenobiotic Clearance Sample Clauses

Cytochrome P450 and Xenobiotic Clearance. From the food we eat, to the air we breathe, and the drugs we take—the human body is constantly being exposed to a myriad of xenobiotic or exogenous substances. While sensing and clearing exogenous compounds is important, our body must also maintain physiological homeostasis to keep the levels of endogenous chemicals such as hormones in balance. The detoxification and elimination of these compounds is mediated through phase I and phase II metabolizing enzymes (Guengerich F. , 1991) (King, 2009). Phase I enzymes primarily introduce new polar groups via oxidation, modify functional groups to become more polar via reduction, or unmask existing polar functional groups xxx xxxxxxxxxx (Xxxxxxxxxx X. , 0000) (King, 2009). Phase II enzymes are typically involved in conjugation reactions with the addition of a new group (King, 2009). Overall, phase I enzymes increase the polarity of compounds leading to excretion or subsequent biotransformation by phase II enzymes (Guengerich F. , 1991). Cytochrome P450s (CYPs), are phase I metabolizing enzymes that are primarily responsible for the biotransformation and elimination of xenobiotics (e.g. environmental pollutants, drugs) and the metabolism of endogenous compounds (e.g. steroids, fatty acids, cholesterol). Cytochrome P450s are a superfamily of heme-containing monoxygenases that are found primarily in the lipid bilayer of the endoplasmic reticulum of hepatocytes (Guengerich F. , 1992). P450s are organized into families based on amino acid homology and families are given a numerical designation—i.e. 1, 2, or 3. These families are further subdivided into subfamilies designated by capital letters—i.e. A, B, or C. Members within these subfamilies are delineated by numbers that represent an individual gene (Guengerich F. , 2010) (King, 2009) (Bibi, 2008) (Figure 1.1). Families 1, 2, and 3 are primarily involved in drug metabolism and metabolize over 70 % of clinical drugs (King, 2009). Figure 1.1: Nomenclature for Cytochrome P450s. CYPs feature wide diversity in catalytic ability and can be induced by the same compounds that they metabolize. CYP inducers trigger the transcription of more CYP proteins. This ensures rapid detoxification of potentially harmful substances (Guengerich F. , 1991) (Guengerich F. , 2010). Understanding the induction of these microsomal enzymes via different compounds, and their interactions with one another, is important for developing novel therapeutics as well as predicting possible drug-drug int...