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

Michel Kranendonk, Christopher C. Marohnic, Satya P. Panda, Maria Paula Duarte, José Santos Oliveira, Bettie Sue Siler Masters, José Rueff

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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: PORnull, PORwt, PORYH, and PORVE, for which equivalent CYP1A2 and CYPOR levels were confirmed, except for PORnull, 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 PORYH and PORVE models than in PORwt, indicating that CYP1A2, and likely other drug-metabolizing CYPs, are impaired by ABS-related POR mutations as observed in the steroidogenic CYPs.

Original languageEnglish (US)
Pages (from-to)93-99
Number of pages7
JournalArchives of Biochemistry and Biophysics
Volume475
Issue number2
DOIs
StatePublished - Jul 15 2008

Keywords

  • Adverse drug reactions
  • Antley-Bixler syndrome
  • CYP1A2
  • Cytochrome P450
  • Drug-metabolizing enzymes
  • NADPH-cytochrome P450 oxidoreductase
  • P450 1A2
  • POR
  • Polymorphism
  • Protein-protein interaction

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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