Journal
DRUG METABOLISM REVIEWS
Volume 39, Issue 2-3, Pages 627-637Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/03602530701467708
Keywords
cytochrome P450; orphan enzymes; drug metabolism; bioactivation; carcinogenesis
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Funding
- NATIONAL CANCER INSTITUTE [R37CA090426] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [P30ES000267] Funding Source: NIH RePORTER
- NCI NIH HHS [R37 CA090426] Funding Source: Medline
- NIEHS NIH HHS [P30 ES000267] Funding Source: Medline
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Of the 57 human cytochromes P450 (P450) and 58 pseudogenes discovered to date, (http:// drinelson.utmem.edu/CytochromeP450.html), 1/4 still remain orphans in the sense that their function, expression sites, and regulation are still largely not elucidated. The posthuman genome-sequencing project era has presented the research community with novel challenges. Despite many insights gathered about gene location and genetic variations in our human genome, we still lack important knowledge about these novel P450 enzymes and their functions in endogenous and exogenous metabolism, as well as their possible roles in the metabolism of toxicants and carcinogens. Our own list of such orphans currently consists of 13 members: P450 2A7, 2S1, 2U1, 2W1, 3A43, 4A22, 4F11, 4F22, 4V2, 4X1, 4Z1, 20A1, and 27C1. Some of the orphans, e.g. P450s 2W1 and 2U1, already have putative assigned functions in arachidonic acid metabolism and may activate carcinogens. However, at this point, for the majority of them more knowledge is available about their genes and single nucleotide polymorphisms than of their biological functions. It is noteworthy that most P450 orphans express high interspecies sequence conservation and have orthologs in rodents (e.g. CYP4X1/Cyp4x1, CYP4V2/Cyp4v3). This review summarizes recent knowledge about the P450 orphans and questions remaining about their specific roles in human metabolism.
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