Antigenotoxic effect of Xanthohumol in rat liver slices.
Xanthohumol (XN), the principal prenylated flavonoid in the hop plant, Humulus lupulus L., is suggested to have cancer chemo-preventive activities. Its mechanisms of protection have been proposed to be inhibition of metabolic activation, induction of detoxifying enzymes and antioxidant activity. Our previous study showed that XN efficiently protected human hepatoma HepG2 cells against the genotoxic effects of two pro-carcinogens (2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and benzo(a)pyrene (BaP)) that are dependent on cytochrome P450 (CYP) mediated metabolic activation, and against genotoxic effects of the oxidative damage inducing tert-butyl hydroperoxide (tBOOH). In the present study, we investigated the antigenotoxic effects of XN in precision-cut rat liver slices. Using the comet assay, we detected that at non-cytotoxic concentrations (0.01-10 microM) XN completely prevented IQ and BaP-induced DNA damage. The protective effects of XN against tBOOH-induced DNA damage was less efficient; the maximal 50% reduction of DNA damage was observed at 0.1 microM XN. In rat microsomes, XN (0.001-10 microM) inhibited CYP1A activity (7-ethoxycoumarin (7EC) de-ethylation) in a concentration-dependent manner. Surprisingly, no inhibition of 7EC metabolism by XN was observed in rat liver slices. XN also did not have any influence on mRNA expression of the enzymes CYP1A2 and quinone reductase (QR). These results indicate that inhibition of metabolic activation of pro-carcinogens by CYP1A is not likely to be the mechanism of its antigenotoxic action. In conclusion, XN efficiently protects DNA against genotoxicity of IQ and BaP and against oxidative DNA damage. Although the mechanism of the protective effect of XN is unclear, our results indicate that XN exhibits antigenotoxic effects in fresh liver tissue and provide additional evidence for the cancer preventive potential of XN.
Plazar
Janja
J
Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. janja.plazar@gmail.com
Filipic
Metka
M
Groothuis
Geny M M
GM
D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism; D020552:Comet Assay; D003374:Coumarins / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D004249:DNA Damage / Q000187:drug effects; D005419:Flavonoids; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D011427:Propiophenones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016587:Antimutagenic Agents; D002273:Carcinogens; D003374:Coumarins; D005419:Flavonoids; D011427:Propiophenones; D012333:RNA, Messenger; C017299:7-ethoxycoumarin; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D016660:NAD(P)H Dehydrogenase (Quinone); C104536:xanthohumol