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The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis

Nature Reviews Cancer volume 6, pages 947–960 (2006)Cite this article

Key Points

  • The metabolism of xenobiotics by xenobiotic-metabolizing enzymes (XMEs) has been classified into phase I (functionalization) and phase II (conjugation) reactions. Cytochrome P450 (CYP) enzymes comprise 70–80% of all phase I XMEs.

  • Although originally thought to be responsible for drug metabolism almost exclusively in the liver, it has now been realized that all XMEs participate in many crucial endogenous functions, probably in every eukaryotic cell and many prokaryotes.

  • Of the 57 human CYP genes in 18 families, the members of the CYP1 to CYP4 families oxygenate thousands of xenobiotics (and endogenous substrates), whereas all members of the CYP5 family and higher principally metabolize endogenous substrates in a highly substrate-specific manner.

  • CYP enzymes can cause tumour initiation through the formation of reactive intermediates (from exogenous and endogenous substrates). CYPs also participate in tumour initiation and progression through inflammation, other eicosanoid-mediated processes and other signal-transduction pathways.

  • There is an interesting 'xenosensor' relationship that is not yet well understood among CYPs, XME receptors that regulate CYP expression and xenobiotic-related transporters (XRTs).

  • Although several high-penetrance, predominantly monogenic (hPpM), traits including cancer have been correlated with various human CYP genes, the identification of a specific procarcinogen is rarely possible.

  • Pharmacokinetic studies of several environmental toxicants in Cyp1 knockout mouse lines have shown that CYP1A1, CYP1A2 and CYP1B1 might be beneficial or detrimental — depending on their time-specific, organ-specific, tissue-specific and cell-type-specific expression. These new findings suggest that animal studies and human epidemiological studies might need to be revisited.

  • Whereas oral drugs more commonly use the portal vein system (and first-pass elimination kinetics), we suggest that the lymphatic system might be more important in delivering the very hydrophobic oral polycyclic aromatic hydrocarbons (PAHs) and polyhalogenated aromatic hydrocarbons (PHAHs) to target tissues. This is especially relevant to clinical medicine, because oral exposure to these procarcinogens is the most predominant route. More focus on pharmacokinetic and pharmacodynamic studies of hydrophobic procarcinogens in animal models (and extrapolation to humans) is needed.

  • A two-tiered model is proposed for the risk of developing cancer as a result of the environment. First, human inter-individual differences in the up-front hPpM traits, encoded by phase I genes, should have profound effects on a small (5–15%) proportion of any population who have no significant polymorphisms in downstream target genes. Second, all downstream targets of phase-I-mediated reactive intermediates can have their own important polymorphisms, always resulting in a unimodal gradient response.

Abstract

Some cytochrome P450 (CYP) heme-thiolate enzymes participate in the detoxication and, paradoxically, the formation of reactive intermediates of thousands of chemicals that can damage DNA, as well as lipids and proteins. CYP expression can also affect the production of molecules derived from arachidonic acid, and alters various downstream signal-transduction pathways. Such changes can be precursors to malignancy. Recent studies in mice have changed our perceptions about the function of CYP1 enzymes. We suggest a two-tiered system to predict an overall inter-individual risk of tumorigenesis based on DNA variants in certain 'early defence' CYP genes, combined with polymorphisms in various downstream target genes.

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Figure 1: Classical schemes.
Figure 2: The distribution of CYP2D6 metabolic ratio values in cigarette smokers with and without lung cancer.
Figure 3: CYP1–AHR 'regulatory-loop' paradigm.

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Acknowledgements

We thank our colleagues, especially L.F. Jorge-Nebert, for valuable discussions and careful readings of this manuscript. This work was funded in part by US National Institutes of Health grants.

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Authors and Affiliations

  1. Department of Environmental Health, and Center for Environmental Genetics, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, 45267-0056, Ohio, USA

    Daniel W. Nebert & Timothy P. Dalton

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  1. Daniel W. Nebert
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Correspondence to Daniel W. Nebert.

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DATABASES

National Cancer Institute

lung cancer

FURTHER INFORMATION

Dan Nebert's homepage

Cytochrome P450 homepage

Human Cytochrome P450 Allele Nomenclature Committee

Indiana University Drug Interaction table

PharmGKB web site

HUGO gene nomenclature homepage

Glossary

Xenobiotic

A foreign chemical in the body. Any chemical, including drugs and foodstuffs, normally located outside the living organism, which exists in the organism (the opposite of an endogenous compound).

Eicosanoid

Any of the many physiologically active substances derived from arachidonic acid — including the prostaglandins, leuko-trienes, prostacyclins and thromboxanes — that are involved in many crucial life functions.

Inborn errors of metabolism

The term coined by A. Garrod in 1908 applying to heritable disorders of biochemistry. Examples include albinism and phenylketonuria.

Hydrophilic

To have a strong affinity for water, which is a property of polar molecules.

Reactive oxygenated intermediates

Chemicals, into which an atom of oxygen has been inserted. ROMs are relatively unstable and degrade quickly by reacting with, and binding covalently to, nucleic acids and proteins.

Genotoxicity

DNA damage. Many reactive oxygenated intermediates attack DNA, and either covalently bind to it to form adducts or produce oxidative stress, which can cause strand breaks and other chromosomal damage.

Xenobiotic-metabolizing enzymes

Enzymes that can metabolize a foreign chemical. It has been suggested that no XME exists for the metabolism of xenobiotics alone, that is, all XMEs have one or more endogenous substrates or functions. Often regulated by 'xenobiotic-sensing' receptors.

Xenobiotic-related transporters

Membrane-bound transporters that move endobiotics (and xenobiotics) across membranes, but which are also regulated by 'xenobiotic-sensing' receptors.

Pharmacokinetics

What the body does to a drug (or other exogenous chemical), encompassing absorption, distribution, metabolism and excretion. Sometimes called 'toxicokinetics'.

Pharmacodynamics

What a drug (or other exogenous chemical) does to the body, encompassing the biochemical and physiological effects and the mechanisms of drug or chemical action. Sometimes called 'toxicodynamics'.

Detoxication

Whereas various enzymes might be described as 'detoxifying a chemical substrate', R.T. Williams, in the 1940s, chose the term 'detoxication' to describe all detoxifying pathways in intact animals.

Procarcinogens

Chemicals capable of causing cancer, but which first require metabolic activation.

Electrophile

Molecules that are electron-deficient, and that are therefore attracted to other molecules (for example, nucleic acids and proteins) at a position where there is a net negative charge.

Hydrophobic

To have little affinity or to be repelled by water, a property of lipophilic ('fat loving') or nonpolar molecules.

Monogenic

Reflecting the properties of a single gene.

Penetrance

The penetrance of a gene refers to the proportion of individuals who, having a defined genotype, manifest a particular trait.

Multiplex phenotype

A trait caused by two or more genes and environmental factors.

Polycyclic aromatic hydrocarbons

Chemicals that contain only C and H atoms arranged in three or more rings (cycles), and that have conjugating double bonds (φ electrons), that is, not saturated. Benzo[α]pyrene (BaP) is a prototypic example. Found in industrial incineration products, cigarette smoke and charcoal-grilled food.

Aflatoxin B1

A potent toxin (C17H12O6) produced by the Aspergillus flavus group of fungi, which causes liver toxicity and cancer in mammals, birds and fish; it also causes mutations, birth defects and immunosuppression in animals. Found as a contaminant in peanuts, cottonseed meal, corn and other grains.

Polyhalogenated aromatic hydrocarbons

Chemicals comprised of C, H, and Cl, Br or F, and sometimes O atoms that are found in toxic waste dump sites and contaminated water; originating from insulators, combustion, refrigeration and other industrial processes. Polychlorinated biphenyls (PCBs) are a prototypic class of PHAHs. PHAHs can be either coplanar or non-coplanar.

Colupulone

The chemical in hops that gives beer its antibiotic properties.

Microsomes

An endoplasmic-reticulum-enriched preparation, produced by separating out cellular subfractions in an ultracentrifuge.

Ductus venosus

The blood vessel, located within the fetal liver, that connects (shunts) the umbilical vein to the inferior vena cava; at the time of birth, changes in the amount of oxygen in the blood and arterial–venous pressure normally close this shunt.

Methemoglobinemia

A condition in which the iron in the haemoglobin molecule (the red blood pigment) is oxidized, making it unable to carry oxygen effectively to the tissues.

Endobiotic

An endogenous compound. Any molecule that is normally expected to be located inside the organism (the opposite of xenobiotic).

Recombineering

The method by which highly efficient bacteriophage-based Escherichia coli homologous recombination sequences (as short as 35–50 bp) can enable genomic DNA in bacterial artificial chromosomes (BACs) to be modified and subcloned, without the need for restriction enzymes or DNA ligases. This new form of chromosome engineering is efficient and significantly reduces the time it takes to create transgenic mouse models compared with traditional methods.

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Nebert, D., Dalton, T. The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer 6, 947–960 (2006). https://doi.org/10.1038/nrc2015

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