Clinical importance of the cytochromes P450

doi:10.1016/S0140-6736(02)11203-7

The Lancet

Volume 360, Issue 9340, 12 October 2002, Pages 1155-1162

https://doi.org/10.1016/S0140-6736(02)11203-7 Get rights and content

Summary

The human cytochrome P450 (CYP) superfamily comprises 57 genes. These genes code for enzymes that can have a role in: metabolism of drugs, foreign chemicals, arachidonic acid and eicosanoids; cholesterol metabolism and bile-acid biosynthesis; steroid synthesis and metabolism; vitamin D₃ synthesis and metabolism; retinoic acid hydroxylation; and those of still unknown function. Cytochrome P450 was once believed to be mainly a hepatic drug detoxication system, but is now understood to include a myriad of enzymic reactions implicated in important life processes. Mutations in many CYP genes cause inborn errors of metabolism and contribute to many clinically relevant diseases.

Section snippets

Foreign chemicals

Foreign chemicals (sometimes called xenobiotics) include drugs, plant-derived or fungal-derived secondary metabolites consumed with food, and thousands of environmental pollutants—eg, halogenated hydrocarbons, polycyclic aromatic hydrocarbons, arylamines, ingredients of combustion, industrial complex mixtures, herbicides, pesticides, etc. Human cytochromes P450 that metabolise these foreign chemicals are almost exclusively in the CYP1, CYP2, CYP3, and to a lesser degree, CYP4 families. Many

Cholesterol metabolism and bile-acid biosynthesis

At least seven, possibly nine, cytochrome P450 enzymes have a role in conversion of acetate into sterols and bile acids (figure 2). Lanosterol 14α-desmethylase, which is encoded by the CYP51A1 gene, is pivotal in the synthesis of cholesterol, removing two methyl groups via oxidative reactions from the intermediate lanosterol. The CYP51A1 enzyme is the target of antifungal drugs such as ketoconazole, and is one of the most evolutionarily conserved of all cytochromes P450. Genes encoding this

Steroid synthesis and metabolism

Six cytochrome P450 enzymes participate in steroidogenesis (figure 3). During sexual differentiation of the genital ridge in early embryogenesis, the transcription factor steroid-factor-1, a member of the nuclear hormone receptor gene family, is pivotal in upregulation of P450 genes implicated in steroid hormone synthesis—including members of the CYP11, CYP17, CYP19, and CYP21 families.⁵⁹ CYP11A1, CYP11B1, and CYP11B2 are mitochondrial enzymes. CYP17A1 is needed for synthesis of cortisol and

Vitamin D₃ synthesis and metabolism

Four P450 enzymes, including three located in mitochondria and one in the endoplasmic reticulum, participate in synthesis and breakdown of 1α,25-dihydroxyvitamin D₃, the ligand of the vitamin D₃ receptor, which is a member of the nuclear hormone receptor superfamily. This receptor-ligand system is responsible for promotion of the export of calcium from bone and absorption of calcium from the gastrointestinal tract (figure 4). CYP27A1 and porcine CYP2D25 are mitochondrial and microsomal enzymes,

Retinoic acid hydroxylation

The CYP26 gene family has three genes, one in each of three subfamilies, suggesting that these genes arose from a common ancestor at least 150–200 million years ago. All three catalyse hydroxylation of retinoic acid (vitamin A). CYP26A1 is an all-trans-retinoic acid hydroxylase that does not act on 9-cis or 13-cis retinoic acid. Retinoic acid is an important morphogen during vertebrate development, operating via several retinoic acid receptors and retinoid X receptors.⁷⁰ As is true of many

Cytochrome P450 enzymes of unknown function

Functions of several cytochromes P450— including CYP20A1, CYP27C1, CYP4A20, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP26B1, and CYP26C1 enzymes—are unknown or, at best, sketchy. The dearth of information associated with these proteins is mainly attributable to their method of identification, which largely concerned database searches of the human genome.4, 7 Some of these genes might have only very limited tissue-specific or cell type-specific distributions, be transiently expressed, or both

Looking to the future

As more and more CYP gene products are analysed, it seems highly likely that their roles in diverse biological systems will expand. Genes in the CYP superfamily are highly polymorphic,⁷¹ as is true of most (if not all) other genes in the human genome,71, 72 and with P450 genetic differences will come interindividual variation in phenotype, with the attendant results for medicine and treatment. In the near future, many more studies are anticipated that will show associations between CYP variant

Search strategy and selection criteria

Medline and PubMed databases from 1966 until April, 2002, were searched for P450 reviews and primary articles related to the CYP genes, CYP enzyme metabolism of both endogenous and exogenous substrates, and relevance to clinical disease. Specific keywords we used included cytochrome P450 metabolism and: drugs, xenobiotics, environmental chemicals, toxicity, cancer, endogenous substrates, evolution, arachidonic acid, eicosanoids, cholesterol, bile acids, steroids, sterols, vitamin D₃,

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ReviewClinical importance of the cytochromes P450

Summary

Section snippets

Foreign chemicals

Cholesterol metabolism and bile-acid biosynthesis

Steroid synthesis and metabolism

Vitamin D3 synthesis and metabolism

Retinoic acid hydroxylation

Cytochrome P450 enzymes of unknown function

Looking to the future

Search strategy and selection criteria

Gene

Trends Genet

Lancet

Mutat Res

Biochem Pharmacol

J Biol Chem

Toxicol Appl Pharmacol

Biochem Biophys Res Commun

Mutat Res

Trends Genet

Arch Biochem Biophys

Biochim Biophys Acta

Arch Biochem Biophys

J Pharm Sci

Gen Pharmacol

J Biol Chem

Biochem Pharmacol

Clin Chest Med

Biochem Biophys Res Common

J Biol Chem

J Biol Chem

Cell

Best Pract Res Clin Endocrinol Metab

J Biol Chem

Mol Cell Endocrinol

J Steroid Biochem Mol Biol

P450 genes: structure, evolution and regulation

Annu Rev Biocliem

The P450 gene superfamily: recommended nomenclature

DMA

Cytochrome P450 gene superfamily

The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names, and nomenclature

DMA Cell Biol

The evolution of drug metabolism

Pharmacology

Induction of cytochromes P450

Curr Drug Metab

Heterotropic cooperativity of cytochrome P450 3A4 and potential drug-drug interactions

Curr Drug Metab

Human cytochrome P450 (CYP) alleles

Pharmacogenomics: the inherited basis for interindividual differences in drug response

Annu Rev Genomics Hum Genet

Review
Clinical importance of the cytochromes P450

Vitamin D₃ synthesis and metabolism