Cytochrome P450 Enzyme System

The cytochrome P450 (CYP) system is a superfamily of haem-thiolate monooxygenases — named for the characteristic 450 nm absorbance of their carbon-monoxide-bound form — that catalyses the majority of oxidative Phase I drug metabolism. A small number of isoforms, particularly CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A2, account for the metabolism of most clinically used drugs.

Definition

The cytochrome P450 enzyme system is a superfamily of membrane-bound haem-containing monooxygenases that, using molecular oxygen and NADPH, oxidise a wide range of endogenous and foreign compounds and carry out most Phase I oxidative drug metabolism.

Scope

This topic covers the structure and catalytic function of cytochrome P450 enzymes, the principal drug-metabolising isoforms, and the mechanisms of enzyme induction and inhibition that make the system a central source of drug-drug interactions and variability. It is educational and gives no dosing advice.

Core questions

• What is the catalytic mechanism of a cytochrome P450 monooxygenase?
• Which CYP isoforms metabolise most clinically used drugs?
• How do enzyme induction and inhibition alter CYP-mediated metabolism?
• Why is the CYP system a major site of drug-drug interactions?

Key concepts

• Haem-thiolate monooxygenase
• Major drug-metabolising isoforms (CYP3A4, 2D6, 2C9, 2C19, 1A2)
• Enzyme induction
• Enzyme inhibition (competitive and mechanism-based)
• NADPH-cytochrome P450 reductase coupling
• Substrate, inhibitor, and inducer relationships
• Tissue expression (hepatic and intestinal)

Mechanisms

Cytochrome P450 enzymes are haem-thiolate proteins anchored largely in the endoplasmic reticulum of hepatocytes and enterocytes. Using electrons delivered by NADPH-cytochrome P450 reductase, they activate molecular oxygen and insert one oxygen atom into a substrate while reducing the other to water, catalysing hydroxylations, dealkylations, and heteroatom oxidations (Guengerich, 1999). Although the human genome encodes many CYPs, a handful of isoforms in the CYP1, CYP2, and CYP3 families perform most drug oxidations, with CYP3A4 the single most important by breadth of substrates (Guengerich, 1999; Zanger & Schwab, 2013). Their activity is highly variable: it can be raised by inducers that increase enzyme expression and lowered by competitive or mechanism-based inhibitors, and it differs between individuals because of genetic polymorphism and regulation (Zanger & Schwab, 2013). Because many drugs are substrates, inhibitors, or inducers of the same isoform, the CYP system is the principal locus of metabolic drug-drug interactions and a major determinant of between-patient variability (Wilkinson, 2005; Rettie & Jones, 2005).

Clinical relevance

CYP induction, inhibition, and genetic variation account for many drug-drug interactions and for much of the variability in drug exposure between individuals. This entry describes these mechanisms as reference background and does not provide interaction-management or dosing instructions for any patient.

Evidence & guidelines

Regulatory frameworks for evaluating metabolic drug-drug interactions are organised around the major cytochrome P450 isoforms. The catalytic chemistry, the dominant role of CYP3A4, and the impact of regulation and genetic variation are documented in comprehensive reviews (Guengerich, 1999; Zanger & Schwab, 2013), with isoform-specific syntheses for clinically important enzymes such as CYP2C9 (Rettie & Jones, 2005).

History

The pigment absorbing at 450 nm when reduced and bound to carbon monoxide was identified in liver microsomes in the late 1950s and 1960s and shown to be a haemoprotein responsible for oxidative drug metabolism. Subsequent decades resolved the superfamily into distinct gene families and isoforms and established CYP3A4 as the predominant human drug-metabolising enzyme (Guengerich, 1999), with later work integrating regulation and pharmacogenetic variation (Zanger & Schwab, 2013).

Key figures

• F. Peter Guengerich
• Ulrich M. Zanger
• Allan E. Rettie

Seminal works

• guengerich-1999
• zanger-schwab-2013

Frequently asked questions

Why is the cytochrome P450 system so important in drug metabolism?

The CYP superfamily catalyses the majority of oxidative Phase I reactions for clinically used drugs, and a few isoforms — led by CYP3A4 — handle most of that work. Because these enzymes can be induced or inhibited and vary genetically, they are a major source of drug-drug interactions and of variability in drug exposure.

What is the difference between an inducer and an inhibitor of a CYP enzyme?

An inducer increases the amount or activity of the enzyme, tending to speed metabolism of its substrates, whereas an inhibitor blocks the enzyme, tending to slow metabolism and raise exposure to its substrates.