TY - JOUR
T1 - Impairment of human CYP1A2-mediated xenobiotic metabolism by Antley-Bixler syndrome variants of cytochrome P450 oxidoreductase
AU - Kranendonk, Michel
AU - Marohnic, Christopher C.
AU - Panda, Satya P.
AU - Duarte, Maria Paula
AU - Oliveira, José Santos
AU - Masters, Bettie Sue Siler
AU - Rueff, José
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2008/7/15
Y1 - 2008/7/15
N2 - 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.
AB - 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.
KW - Adverse drug reactions
KW - Antley-Bixler syndrome
KW - CYP1A2
KW - Cytochrome P450
KW - Drug-metabolizing enzymes
KW - NADPH-cytochrome P450 oxidoreductase
KW - P450 1A2
KW - POR
KW - Polymorphism
KW - Protein-protein interaction
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U2 - 10.1016/j.abb.2008.04.014
DO - 10.1016/j.abb.2008.04.014
M3 - Article
C2 - 18455494
AN - SCOPUS:44949214648
VL - 475
SP - 93
EP - 99
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
SN - 0003-9861
IS - 2
ER -