title: Dual effects of phloretin on aflatoxin B1 metabolism: activation and detoxification of aflatoxin B1.
abstract: Typically, chemopreventive agents involve either induction of phase II detoxifying enzymes and/or inhibition of cytochrome P450 enzymes (CYPs) that are required for the activation of procarcinogens. In this study, we investigated the protective effects of phloretin against aflatoxin B1 (AFB1) activation to the ultimate carcinogenic intermediate, AFB(1)-8, 9-epoxide (AFBO), and its subsequent detoxification. Phloretin markedly inhibited formation of the epoxide with human liver microsomes in a dose-dependent manner. Phloretin also inhibited the activities of nifedipine oxidation and ethoxyresorufin O-deethylase (EROD) in human liver microsomes. These data show that phloretin strongly inhibits CYP1A2 and CYP3A4 activities, which are involved in the activation of AFB1. Phloretin increased glutathione S-transferase (GST) activity of alpha mouse liver 12 (AML 12) cells in a dose-dependent manner. GST activity toward AFBO in cell lysates treated with 20 μM phloretin was 23-fold that of untreated control cell lysates. The expression of GSTA3, GSTA4, GSTM1, GSTP1 and GSTT1 was induced by phloretin in a dose-dependent manner in AML 12 cells. GSTP1, GSTM1, and GSTT1 were able to significantly increase the conjugation of AFBO with glutathione. Concurrently, induction of the GST isozyme genes was partially associated with the Nrf2/ARE pathway. Taken together, the results demonstrate that phloretin has a strong chemopreventive effect against AFB1 through its inhibitory effect on CYP1A2, CYP3A4, and its inductive effect on GST activity.
authors.affiliation: Vestibulocochlear Research Center and Department of Biochemistry, School of Medicine, Wonkwang University, Chollabuk-Do, Republic of Korea.
authors.forename: Shang Shang
authors.initials: SS
authors.lastname: Gao
authors.forename: Xiao Yan
authors.initials: XY
authors.lastname: Chen
authors.forename: Ri Zhe
authors.initials: RZ
authors.lastname: Zhu
authors.forename: Byung-Min
authors.initials: BM
authors.lastname: Choi
authors.forename: Sun Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Bok-Ryang
authors.initials: BR
authors.lastname: Kim
mesh_terms: D016604:Aflatoxin B1 / Q000493:pharmacokinetics*; D000818:Animals; D002460:Cell Line; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004790:Enzyme Induction / Q000187:drug effects; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010693:Phloretin / Q000493:pharmacokinetics* / Q000494:pharmacology; D020218:Response Elements
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D007527:Isoenzymes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016604:Aflatoxin B1; D008156:Luciferases; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D005982:Glutathione Transferase; D010693:Phloretin