Impairment of human CYP1A2-mediated xenobiotic metabolism by Antley–Bixler syndrome variants of cytochrome P450 oxidoreductase

Y459H and V492E mutations of cytochrome P450 reductase (CYPOR) cause Antley–Bixler syndrome due to diminished binding of the FAD cofactor. To address whether these mutations impaired the interaction with drug-metabolizing CYPs, a bacterial model of human liver expression of CYP1A2 and CYPOR was impl...

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Veröffentlicht in:Archives of biochemistry and biophysics 2008-07, Vol.475 (2), p.93-99
Hauptverfasser: Kranendonk, Michel, Marohnic, Christopher C., Panda, Satya P., Duarte, Maria Paula, Oliveira, José Santos, Masters, Bettie Sue Siler, Rueff, José
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Sprache:eng
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Zusammenfassung:Y459H and V492E mutations of cytochrome P450 reductase (CYPOR) cause Antley–Bixler syndrome due to diminished binding of the FAD cofactor. To address whether these mutations impaired the interaction with drug-metabolizing CYPs, a bacterial model of human liver expression of CYP1A2 and CYPOR was implemented. Four models were generated: POR null, POR wt, POR YH, and POR VE, for which equivalent CYP1A2 and CYPOR levels were confirmed, except for POR null, not containing any CYPOR. The mutant CYPORs were unable to catalyze cytochrome c and MTT reduction, and were unable to support EROD and MROD activities. Activity was restored by the addition of FAD, with V492E having a higher apparent FAD affinity than Y459H. The CYP1A2-activated procarcinogens, 2-aminoanthracene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and 2-amino-3-methylimidazo(4,5- f)quinoline, were significantly less mutagenic in POR YH and POR VE models than in POR wt, indicating that CYP1A2, and likely other drug-metabolizing CYPs, are impaired by ABS-related POR mutations as observed in the steroidogenic CYPs.
ISSN:0003-9861
1096-0384
DOI:10.1016/j.abb.2008.04.014