TY - JOUR
T1 - The mechanism of inhibition of cytochrome P450IIE1 by dihydrocapsaicin
AU - Gannett, Peter M.
AU - Iversen, Patrick
AU - Lawson, Terence
N1 - Funding Information:
This work was supported by grants from the NIH ROl CA40989-01, thank Dr. P. Cresmonesi for his aid in the preparative electrochemical lieri for the use of his electrochemical apparatus.
PY - 1990/6
Y1 - 1990/6
N2 - Dihydrocapsaicin (2) is a noncompetitive inhibitor of cytochrome P450IIE1. This was demonstrated by studying the inhibition of p-nitrophenol oxidation. The covalent binding of 2 to cytochrome P450IIE1 was examined by incubating tritiated 2 with rat liver microsomes and gel electrophoresis of the resulting bound cytochrome P450 isozymes. Autoradiograms of these gels displayed a single band at approximately 48 kDa. The mechanism whereby 2 became covalently bonded to cytochrome P450IIE1 was explored by studying the oxidation of 2 by electrochemical, chemical, and enzymatic methods. Oxidation of 2 by all methods generally resulted in the formation of the 5,5′-dimer of 2, 4, which likely forms by dimerization of the phenoxy radical 7. It is suggested that 2 is oxidized to 7 by cytochrome P450IIE1 and 7 then covalently bonds to cytochrome P450IIE1 thereby inactivating it.
AB - Dihydrocapsaicin (2) is a noncompetitive inhibitor of cytochrome P450IIE1. This was demonstrated by studying the inhibition of p-nitrophenol oxidation. The covalent binding of 2 to cytochrome P450IIE1 was examined by incubating tritiated 2 with rat liver microsomes and gel electrophoresis of the resulting bound cytochrome P450 isozymes. Autoradiograms of these gels displayed a single band at approximately 48 kDa. The mechanism whereby 2 became covalently bonded to cytochrome P450IIE1 was explored by studying the oxidation of 2 by electrochemical, chemical, and enzymatic methods. Oxidation of 2 by all methods generally resulted in the formation of the 5,5′-dimer of 2, 4, which likely forms by dimerization of the phenoxy radical 7. It is suggested that 2 is oxidized to 7 by cytochrome P450IIE1 and 7 then covalently bonds to cytochrome P450IIE1 thereby inactivating it.
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U2 - 10.1016/0045-2068(90)90041-3
DO - 10.1016/0045-2068(90)90041-3
M3 - Article
AN - SCOPUS:0025031845
SN - 0045-2068
VL - 18
SP - 185
EP - 198
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
IS - 2
ER -