The human genome project and novel aspects of cytochrome p450 research

Toxicology and Applied Pharmacology 207 (2005) S52 – S56 www.elsevier.com/locate/ytaap

Review

The human genome project and novel aspects of cytochrome P450 research
Magnus Ingelman-Sundberg*
Division of Molecular Toxicology, IMM, Karolinska Institutet, SE-171 77 Stockholm, Sweden Received 16 August 2004; revised 3 January 2005; accepted 3 January 2005 Available online 1 July 2005Abstract Currently, 57 active cytochrome P450 (CYP) genes and 58 pseudogenes are known to be present in the human genome. Among the genes discovered by initiatives in the human genome project are CYP2R1, CYP2W1, CYP2S1, CYP2U1 and CYP3A43, the latter apparently encoding a pseudoenzyme. The function, polymorphism and regulation of these genes are still to be discovered to a great extent. Thepolymorphism of drug metabolizing CYPs is extensive and influences the outcome of drug therapy causing lack of response or adverse drug reactions. The basis for the differences in the global distribution of the polymorphic variants is inactivating gene mutations and subsequent genetic drift. However, polymorphic alleles carrying multiple active gene copies also exist and are suggested in case of CYP2D6 to becaused by positive selection due to development of alkaloid resistance in North East Africa about 10,000 – 5000 BC. The knowledge about the CYP genes and their polymorphisms is of fundamental importance for effective drug therapy and for drug development as well as for understanding metabolic activation of carcinogens and other xenobiotics. Here, a short review of the current knowledge is given.D 2005 Elsevier Inc. All rights reserved.
Keywords: Ultrarapid metabolizers; Poor metabolizers; Adverse drug reactions; Genetic polymorphism; Vitamin D; Naphtalene; CYP2S1; CYP2R1; CYP2U1

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . Human cytochrome PS450 genes . . . . . . . . . . . . . Evolution of human P450s and P450 variants . . . . . . Functional effects of theinterindividual variability in CYP Conclusions . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S52 S53 S53 S55 S55 S55 S55

Introduction The cytochrome P450 enzymes in families1 –3 are responsible for 70– 80% of all phase I dependent metabolism of clinically used drugs (Evans and Relling, 2004, Ingelman-

* Fax: +46 8 337 327. E-mail address: maging@ki.se. 0041-008X/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.taap.2005.01.030

Sundberg, 2004) and participate in the metabolism of a huge number of xenobiotic chemicals. The polymorphicforms of P450s are many times responsible for the development of adverse drug reactions. Phillips et al. (2001) showed that 56% of drugs which are cited in adverse drug reaction (ADR) studies are metabolized by polymorphic Phase 1 enzymes of which 86% are P450s, whereas only 20% of drugs that are substrates for nonpolymorphic enzymes are in the ADR reports. It has been estimated that: (i) ADRscost the US

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society about 100 billion US$, (ii) they cause more than 100,000 deaths annually in the US and (iii) up to 7% of all hospital admissions are due to ADRs (see IngelmanSundberg, 2001 for references). Knowledge about the cytochrome P450 system is fundamental...