Modulation of diethylnitrosamine-initiated placental glutathione S-transferase positive preneoplastic and neoplastic lesions by clofibrate, a hepatic peroxisome proliferator.
The effect of clofibrate (CF) on proliferation of diethylnitrosamine (DEN)-initiated glutathione S-transferase placental form (GST-P)-positive preneoplastic and neoplastic lesions as studied in male F344 rats. Animals were given a single i.p. injection of 200 mg/kg body weight of DEN, and then from 2 weeks later were given a diet containing 0.3% CF (group 1), or no supplement (group 2) until week 64. Group 3 received an injection of 0.9% NaCl instead of DEN and then a diet containing 0.3% CF, like group 1. Animals in all groups were subjected to partial hepatectomy at week 3 and killed at weeks 8, 20, 32, 49 or 64. The results showed that development of GST-P-positive lesions was significantly less in group 1 than in group 2 from week 8 (P less than 0.05). However, in group 1, morphologically distinguishable GST-P-negative preneoplastic lesions increased from week 20 (P less than 0.05), and the total number of GST-P-positive and -negative lesions was significantly greater than that in group 2 from week 32 (P less than 0.05). The induction of hepatocellular carcinoma (HCC) was greater in group 1 than in group 2 from week 49. All the HCCs induced in group 2 were GST-P-positive, whereas 38.9% (7/18) of those in group 1 were GST-P-negative. In group 3, only a few GST-P-positive and/or -negative preneoplastic lesions developed by week 64. These results suggest that CF has tumor-promoting activity, and that GST-P-positive cells induced by DEN changed to GST-P-negative cells on subsequent treatment with CF.
Hosokawa
S
S
Department of Drug Safety Research, Eisai Co., Ltd, Kawashima Industry Park, Gifu, Japan.
Tatematsu
M
M
Aoki
T
T
Nakanowatari
J
J
Igarashi
T
T
Ito
N
N
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002994:Clofibrate / Q000494:pharmacology*; D004052:Diethylnitrosamine / Q000633:toxicity*; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology; D008115:Liver Regeneration; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000201:enzymology; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344
D007527:Isoenzymes; D004052:Diethylnitrosamine; D005982:Glutathione Transferase; D002994:Clofibrate