Urinary metabolite profiling reveals CYP1A2-mediated metabolism of NSC686288 (aminoflavone)

Chen, Chi; Meng, Linghua; Ma, Xiaochao; Krausz, Kristopher W; Pommier, Yves; Idle, Jeffrey R; Gonzalez, Frank J (2006). Urinary metabolite profiling reveals CYP1A2-mediated metabolism of NSC686288 (aminoflavone). Journal of pharmacology and experimental therapeutics, 318(3), pp. 1330-42. Bethesda, Md.: American Society for Pharmacology and Experimental Therapeutics 10.1124/jpet.106.105213

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NSC686288 [aminoflavone (AF)], a candidate chemotherapeutic agent, possesses a unique antiproliferative profile against tumor cells. Metabolic bioactivation of AF by drug-metabolizing enzymes, especially CYP1A monooxygenases, has been implicated as an underlying mechanism for its selective cytotoxicity in several cell culture-based studies. However, in vivo metabolism of AF has not been investigated in detail. In this study, the structural identities of 13 AF metabolites (12 of which are novel) in mouse urine or from microsomal incubations, including three monohydroxy-AFs, two dihydroxy-AFs and their sulfate and glucuronide conjugates, as well as one N-glucuronide, were determined by accurate mass measurements and liquid chromatography-tandem mass spectrometry fragmentation patterns, and a comprehensive map of the AF metabolic pathways was constructed. Significant differences between wild-type and Cyp1a2-null mice, within the relative composition of urinary metabolites of AF, demonstrated that CYP1A2-mediated regioselective oxidation was a major contributor to the metabolism of AF. Comparisons between wild-type and CYP1A2-humanized mice further revealed interspecies differences in CYP1A2-mediated catalytic activity. Incubation of AF with liver microsomes from all three mouse lines and with pooled human liver microsomes confirmed the observations from urinary metabolite profiling. Results from enzyme kinetic analysis further indicated that in addition to CYP1A P450s, CYP2C P450s may also play some role in the metabolism of AF.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Clinical Pharmacology and Visceral Research (discontinued)

UniBE Contributor:

Idle, Jeffrey

ISSN:

0022-3565

ISBN:

16775196

Publisher:

American Society for Pharmacology and Experimental Therapeutics

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:45

Last Modified:

17 Mar 2015 21:43

Publisher DOI:

10.1124/jpet.106.105213

PubMed ID:

16775196

Web of Science ID:

000239878900048

URI:

https://boris.unibe.ch/id/eprint/18586 (FactScience: 781)

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