Orphans in the Human Cytochrome P450 Superfamily: Approaches to Discovering Functions and Relevance in Pharmacology

Guengerich, F. Peter; Cheng, Qian

doi:10.1124/pr.110.003525

Cited by 81 publications

(58 citation statements)

References 103 publications

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“…The importance of P450s in steroid metabolism is documented by the large number of instances of inherited endocrine diseases now linked to defects in P450 (CYP) genes (4,5). Roughly one-fourth of the human P450s have important roles in steroid metabolism (6,7). The effects of small chemical changes in steroids (introduced by P450s and other enzymes) are rather remarkable in terms of the resulting changes in biological activities.…”

Section: P450mentioning

confidence: 99%

Oxidation of Dihydrotestosterone by Human Cytochromes P450 19A1 and 3A4

Cheng

Sohl

Yoshimoto

et al. 2012

Journal of Biological Chemistry

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Background:The fate of dihydrotestosterone has been characterized only in terms of reduction of the 3-ketone. Results: Human P450s 19A1 and 3A4 oxidized dihydrotestosterone to several new products, detected in vivo. Conclusion:The new P450 19A1 and 3A4 pathways introduce an oxidative dimension to the metabolism of dihydrotestosterone. Significance: Small changes in the steroid A ring can produce major changes in P450 3A4 catalytic selectivity.

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Section: P450mentioning

confidence: 99%

Oxidation of Dihydrotestosterone by Human Cytochromes P450 19A1 and 3A4

Cheng

Sohl

Yoshimoto

et al. 2012

Journal of Biological Chemistry

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“…Cytochrome P450s (P450s) are a superfamily of membraneassociated heme-containing enzymes, for which the human genome contains 57 distinct P450 genes (Ortiz de Montellano, 1995;Guengerich and Cheng, 2011). P450 enzymes represent a well studied and relatively well understood family of enzymes that have been reported as the most important enzymes responsible for the majority of oxidative drug metabolism.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Non-Cytochrome P450-Mediated Metabolism in Food and Drug Administration-Approved Oral and Intravenous Drugs: 2006-2015

Cerny

2016

Drug Metabolism and Disposition

124

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In recent years, claims of increased involvement of non-cytochrome P450 (non-P450) enzymes in the metabolism of drugs have appeared in the literature. However, no temporal summaries of the contribution of non-P450 enzymes to the metabolism of drugs have been published. Using data from human radiolabeled absorption, distribution, metabolism, and excretion studies available for a set of 125 orally or intravenously administered small-molecule drugs approved by the United States Food and Drug Administration from 2006 to 2015, the contributions of P450 and non-P450 enzymes to the formation of major metabolites ( ‡10% of dose) were assessed and tabulated. Over this time frame, the involvement of P450 versus non-P450 enzymes in the formation of major metabolites is compared, and the individual non-P450 enzymes responsible are described. This analysis indicates that non-P450 enzymes contribute significantly to the metabolism of the 125 drugs analyzed. Approximately 30% of the metabolism of these drugs is carried out by non-P450 enzymes, with the predominant non-P450 enzymes identified being glucuronosyltransferases (11.7%), hydrolases (10.8%), carbonyl reductases (2.4%), and aldehyde oxidase (1.1%). Although significant, the relative contribution of non-P450 enzymes to drug metabolism does not appear to have increased dramatically over the last 10 years. As the current evaluation involves drugs which emerged from the discovery phase >10 years ago, this evaluation may not reflect the current or evolving situation in some research organizations; therefore, additional monitoring and assessment of the involvement of non-P450 enzymes in the metabolism of drugs will be conducted in the future.

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“…With Ͼ18,000 known P450 sequences available and the number increasingly rapidly, it is humbling to realize that we understand the functions of only a fraction of these P450s (12). The flexibility of the P450 proteins is now recognized, and prediction of catalytic activities for individual P450s is still difficult.…”

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confidence: 99%

New Trends in Cytochrome P450 Research at the Half-Century Mark

Guengerich

2013

Journal of Biological Chemistry

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Cytochrome P450 enzymes have major roles in the metabolism of steroids, drugs, carcinogens, eicosanoids, and numerous other chemicals. The P450s are collectively considered the most diverse catalysts known in biochemistry, although they operate from a basic structural fold and catalytic mechanism. The four minireviews in this thematic series deal with the unusual aspects of catalytic reactions and electron transfer pathway organization, the structural diversity of P450s, and the expanding roles of P450s in disease and medicine.

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Orphans in the Human Cytochrome P450 Superfamily: Approaches to Discovering Functions and Relevance in Pharmacology

Cited by 81 publications

References 103 publications

Oxidation of Dihydrotestosterone by Human Cytochromes P450 19A1 and 3A4

Oxidation of Dihydrotestosterone by Human Cytochromes P450 19A1 and 3A4

Prevalence of Non-Cytochrome P450-Mediated Metabolism in Food and Drug Administration-Approved Oral and Intravenous Drugs: 2006-2015

New Trends in Cytochrome P450 Research at the Half-Century Mark

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