Genistein as a potential inducer of the anti-atherogenic enzyme paraoxonase-1: studies in cultured hepatocytes in vitro and in rat liver in vivo.
A number of cardioprotective effects, including the reduced oxidation of the low-density lipoprotein (LDL) particles, have been attributed to dietary soy isoflavones. Paraoxonase 1 (PON1), an enzyme mainly synthesized in the liver, may exhibit anti-atherogenic activity by protecting LDL from oxidation. Thus, dietary and pharmacological inducers of PON1 may decrease cardiovascular disease risk. Using a luciferase reporter gene assay we screened different flavonoids for their ability to induce PON1 in Huh7 hepatocytes in culture. Genistein was the most potent flavonoid with regard to its PON1-inducing activity, followed by daidzein, luteolin, isorhamnetin and quercetin. Other flavonoids such as naringenin, cyanidin, malvidin and catechin showed only little or no PON1-inducing activity. Genistein-mediated PON1 transactivation was partly inhibited by the oestrogen-receptor antagonist fulvestrant as well as by the aryl hydrocarbon receptor antagonist 7-ketocholesterol. In contrast to genistein, the conjugated genistein metabolites genistein-7-glucuronide, genistein-7-sulfate and genistein-7,4'-disulfate were only weak inducers of PON1 transactivation. Accordingly, dietary genistein supplementation (2 g/kg diet over three weeks) in growing rats did not increase hepatic PON1 mRNA and protein levels as well as plasma PON1 activity. Thus, genistein may be a PON1 inducer in cultured hepatocytes in vitro, but not in rats in vivo.
Institute of Human Nutrition and Food Science, Christian-Albrechts-University of Kiel, Kiel, Germany.
Charlotte
C
Schrader
Insa M A
IM
Ernst
Heike
H
Sinnecker
Sebastian T
ST
Soukup
Sabine E
SE
Kulling
Gerald
G
Rimbach
D000818:Animals; D043303:Aryldialkylphosphatase / Q000097:blood / Q000378:metabolism*; D002460:Cell Line; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL; D004032:Diet; D019587:Dietary Supplements; D020536:Enzyme Activators / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D007653:Ketocholesterols / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D047311:Luteolin / Q000494:pharmacology; D008297:Male; D010084:Oxidation-Reduction; D011794:Quercetin / Q000031:analogs & derivatives / Q000494:pharmacology; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000378:metabolism; D013025:Glycine max / Q000737:chemistry
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D007529:Isoflavones; D007653:Ketocholesterols; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C047368:3-methylquercetin; C004742:daidzein; D012313:RNA; D011794:Quercetin; D019833:Genistein; D043303:Aryldialkylphosphatase; D047311:Luteolin; C003001:7-ketocholesterol