Cytochrome P450 Superfamily

The cytochrome P450 (CYP) superfamily is a large family of heme-containing enzymes that carries out most of the oxidative metabolism of drugs in the human body. A handful of its members, especially CYP3A4, CYP2D6, CYP2C9, and CYP2C19, are responsible for metabolising a large share of clinically used medicines, and inherited variation in their genes is a leading cause of differences in drug response.

Definition

The cytochrome P450 superfamily comprises heme-thiolate monooxygenase enzymes that catalyse the oxidation of a wide range of endogenous and exogenous compounds, and in pharmacology mediate the principal phase I oxidative metabolism of drugs.

Scope

This topic covers the structure and catalytic role of cytochrome P450 enzymes in drug oxidation, the major drug-metabolizing CYP families and their substrates, and the genetic polymorphisms that define metabolizer phenotypes (poor, intermediate, normal, and ultrarapid). It treats the superfamily as a pharmacogenomic reference subject and does not give prescribing instructions.

Core questions

• Which cytochrome P450 enzymes metabolise a given drug?
• How do genetic variants in CYP genes change enzyme activity and metabolizer phenotype?
• How do CYP enzymes contribute to drug-drug interactions through induction and inhibition?

Key concepts

• Heme-thiolate monooxygenase catalysis
• Major drug-metabolizing isoforms (CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2)
• Star (*) allele nomenclature
• Metabolizer phenotypes: poor, intermediate, normal, ultrarapid
• Substrate, inhibitor, and inducer relationships
• Genotype-to-phenotype translation

Mechanisms

Cytochrome P450 enzymes use a heme iron centre and molecular oxygen, with electrons supplied by NADPH via P450 reductase, to insert an oxygen atom into a substrate - typically hydroxylation or related oxidation. This converts lipophilic drugs into more polar metabolites that can be further conjugated or excreted (Wilkinson, 2005). The genes encoding these enzymes are highly polymorphic: variant alleles (named with a star nomenclature) can abolish, reduce, increase, or duplicate enzyme activity, producing the spectrum of poor, intermediate, normal, and ultrarapid metabolizers. CYP2D6 is a well-studied example whose copy-number and sequence variants span this entire range (Ingelman-Sundberg, 2004). Because a few CYP enzymes handle a large fraction of drugs, the same isoform is often a shared route for multiple medicines, which underlies many metabolic drug-drug interactions (Evans & McLeod, 2003).

Clinical relevance

CYP genotype helps explain why patients given the same drug can experience very different exposures and effects, and CYP-based pharmacogenomic testing is incorporated into published genotype-guided frameworks for several drug classes (Hicks et al., 2017). This entry explains the underlying mechanism for reference; specific dosing is determined by clinicians using current guidelines and is outside its scope.

Epidemiology

CYP variant alleles are common and their frequencies differ substantially across populations; for example, the proportion of poor and ultrarapid CYP2D6 metabolizers varies by ancestry, contributing to population differences in drug response (Ingelman-Sundberg, 2004).

History

Cytochrome P450 was named for the characteristic 450-nanometre absorption peak of its carbon-monoxide-bound reduced form, observed in the early 1960s. Subsequent decades saw the cloning and functional characterisation of the human CYP genes and the discovery that polymorphisms such as those of CYP2D6 explain inherited differences in drug oxidation, work synthesised in the pharmacogenomic reviews of Wilkinson (2005), Ingelman-Sundberg (2004), and Evans and McLeod (2003).

Key figures

• Magnus Ingelman-Sundberg
• Grant Wilkinson
• William Evans
• Howard McLeod

Seminal works

• ingelman-sundberg-2004
• wilkinson-2005
• evans-mcleod-2003

Frequently asked questions

Why are a few cytochrome P450 enzymes so important for drug metabolism?

A small number of CYP isoforms - particularly CYP3A4, CYP2D6, CYP2C9, and CYP2C19 - oxidise a large proportion of commonly used drugs, so variation or interactions affecting these enzymes can influence many medicines at once.

What is a metabolizer phenotype?

It is a classification (poor, intermediate, normal, or ultrarapid metabolizer) summarising how much functional CYP enzyme activity a person has, based on the combination of variant alleles they carry.