Drug Metabolism by CYP450 Enzymes

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Drug Metabolizing Cytochrome P450 Enzymes and Their Inhibitors

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This tutorial covers the basic structure and function of the Cytochrome P450 (CYP or CYP450) enzymes, with particular emphasis on their relevance to drug action. It may be useful as a standalone primer on the basics of CYP metabolism, but is intended to supplement a more comprehensive text, such as Chapter 4 of the 7th edition of Foye's Principles of Medicinal Chemistry[1]. The primary purpose of this page is to graphically illustrate some of the principles of CYP450 metabolism that are otherwise difficult to visualize.

CYP450 enzymes are the most important group of drug metabolizing enzymes. A very large proportion of medications are metabolized primarily through oxidation by various CYP450s. There are more than 50 individual CYP450s, but six are quite significant, as they can metabolize from 75-90% of all drugs [2]. These six include: CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4 and CYP3A5. Other isoforms such as CYP2E1 and CYP1A1 are important to a lesser degree, such as in the context of activation of[procarcinogens. CYP enzymes in families 5 or higher are typically important for processing steroids in humans, rather than drug metabolism. These enzymes are generally known by names other than their CYP designation. For instance, CYP27A1 is known as sterol 27-hydroxylase, and is important for biosynthesis of bile acids. Other CYPs are not found in humans, but may be drug targets. One of these is CYP51A1, or lanosterol 14 alpha-demethylase. This CYP is important for the production of ergosterol in fungi, which serves the same purpose in fungal cell membranes as cholesterol does in humans.

The name of a CYP450 enzyme indicates its similarity in structure to other CYPs. Those with greater than 40% amino acid homology are grouped into families, and those with greater than 55% homology are grouped into subfamilies. There is a systematic method for naming and grouping them, with the letters and numbers referring to families, subfamilies, and individual members. Thus CYP1, CYP2, and CYP3 are separate families. A letter following the family name indicates the particular subfamily. Thus CYP1A1 and CYP1A2 are the first and second members of the CYP1A subfamily, but both belong to the CYP1 family. Individual CYPs, such as CYP1A1, CYP1A2, CYP3A4, and CYP2D6, are referred to as isoforms of each other.

Recognizing the individual CYP responsible for metabolism of a drug can be very important for predicting potentially dangerous results from its co-administration with other drugs. There are several reasons that drugs can have negative interactions based on CYP enzymes. If one drug induces or inhibits a CYP, then another drug metabolized by that same CYP may have increased or decreased levels in the plasma. The result of this might be either toxicity or treatment failure. Interactions are most clinically important in drugs that have a narrow therapeutic range, those that are vital for maintaining a healthy state, and those with important toxicities.

As you go through this tutorial, try to answer each of the questions posed within the text. When you get to the end, write out the answers to the Focused Questions.

Human cytochrome P450 complex with naphthoflavone (PDB code 2hi4)

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Arthur Cox, Michal Harel, Robin Morgan

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