Alpha-benzene hexachloride exerts hormesis in preneoplastic lesion formation of rat hepatocarcinogenesis with the possible role for hepatic detoxifying enzymes.
Recently there has been a shift in the prevailing paradigm regarding the dose dependence of carcinogen action with increasing acceptance of hormesis phenomenon, although underlying mechanisms remain to be established. To ascertain whether alpha-benzene hexachloride (alpha-BHC) might act by hormesis, rats were initiated with diethylnitrosamine and then alpha-BHC ranging from 0.01 to 500 ppm was administered in the diet for 10 weeks. The highest concentration of alpha-BHC significantly increased the number and area of glutathione S-transferase placental form (GST-P) positive foci, preneoplastic lesions in the liver, but its low dose, 0.05 ppm, caused significant reduction, showing a J-shape dose-response curve. The proliferating cell nuclear antigen positive index for GST-P positive foci in the low dose-treated group was significantly reduced. The dose response curves of CYP450 content, NADPH-P450 reductase activity and 8-hydroxydeoxyguanosine formation revealed the same pattern as GST-P positive foci data. The response curves of CYP2B1 and 3A2 in their activities, protein and mRNA expression showed a threshold but CYP2C11 activity exhibited an inverted J-shape. These results might suggest the possibility of hormesis of alpha-BHC at early stages of rat hepatocarcinogenesis. The possible mechanism involves induction of detoxifying enzymes at low dose, influencing free radical production and oxidative stress, and consequently pathological change in the liver.
Puatanachokchai
Rawiwan
R
Department of Pathology, Osaka City University Medical School, Abeno-ku, Asahi-machi 1-4-3, Osaka 545-8585, Japan.
Morimura
Keiichirou
K
Wanibuchi
Hideki
H
Oka
Mayuko
M
Kinoshita
Anna
A
Mitsuru
Fukui
F
Yamaguchi
Shuji
S
Funae
Yoshihiko
Y
Fukushima
Shoji
S
D000080242:8-Hydroxy-2'-Deoxyguanosine / Q000031:analogs & derivatives; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D004249:DNA Damage; D004052:Diethylnitrosamine; D004305:Dose-Response Relationship, Drug; D051549:Glutathione S-Transferase pi / Q000032:analysis / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000032:analysis; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D007306:Insecticides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013739:Testosterone / Q000378:metabolism
D007306:Insecticides; D008565:Membrane Proteins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D004052:Diethylnitrosamine; D013739:Testosterone; D001556:Hexachlorocyclohexane; D006147:Guanine; C078307:8-oxo-7,8-dihydrodeoxyguanine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D009251:NADPH-Ferrihemoprotein Reductase; D051549:Glutathione S-Transferase pi; C496558:Gstp1 protein, rat