Involvement of rat cytochrome 1A1 in the biotransformation of kaempferol to quercetin: relevance to the genotoxicity of kaempferol.
Kaempferol is a flavonoid widely distributed in edible plants and has been shown to be genotoxic to V79 cells in the absence of external metabolizing systems. The presence of an external metabolizing system, such as rat liver homogenates (S9 mix), leads to an increase in its genotoxicity, which is attributed to its biotransformation to the more genotoxic flavonoid quercetin, via the cytochrome P450 (CYP) mono-oxygenase system. In the present work we investigated the mechanisms of the genotoxicity of kaempferol further. Special attention has been given to the role of CYP in the genotoxicity of this flavonoid. We studied the induction of mutations in Salmonella typhimurium TA98 in the presence and in the absence of S9 mix and the induction of chromosomal aberrations (CAs) and micronuclei (MN) by kaempferol in V79 cells in the presence and in the absence of S9 mix. To evaluate the role of different CYP in the biotransformation of kaempferol we studied the induction of CAs and MN in V79 cells genetically engineered for the expression of rat CYP 1A1, 1A2 and 2B1. In addition we performed CYP inhibition studies using the above-mentioned indicators and high performance liquid chromatography (HPLC) analysis. The results obtained in this work suggest that rat CYP 1A1 is, among the cytochromes studied, the one that plays the major role in the transformation of kaempferol into quercetin. The relevance of these findings to the human situation is discussed.
Silva
I D
ID
Department of Genetics, Faculty of Medical Sciences, New University of Lisbon, Portugal.
Rodrigues
A S
AS
Gaspar
J
J
Maia
R
R
Laires
A
A
Rueff
J
J
D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D005419:Flavonoids; D006801:Humans; D044949:Kaempferols; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens; D011794:Quercetin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects; D014162:Transfection
D005419:Flavonoids; D044949:Kaempferols; D009153:Mutagens; D011994:Recombinant Proteins; C006552:kaempferol; D011794:Quercetin; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D019362:Cytochrome P-450 CYP2B1