Lack of hepatotoxicity or promotion of enzyme-altered liver foci development in rats treated with harman or norharman.

The modifying effects of harman or norharman on liver carcinogenesis were investigated in male F344/DuCrj rats initially treated with N-nitrosodiethylamine (DEN). Two weeks after a single dose of DEN (200 mg/kg, intraperitoneally), rats were given harman or norharman at dietary levels of 1000 and 200 parts per million (ppm), or sodium phenobarbital (PB) at 500 ppm as a positive control, for 6 wk. At wk 3 following DEN administration, all animals were subjected to partial hepatectomy. Marked retardation of body weight gain was observed in rats treated with harman or norharman at 1000 ppm, but not at 200 ppm. Increased relative kidney but not liver weights were associated with harman or norharman treatment, especially in the higher dose groups. Although no toxicity-related hepatocyte lesions were found, severe renal toxic tubular lesions and regeneration were evident. Neither harman nor norharman significantly increased the numbers or areas of glutathione S-transferase placental form (GST-P) positive foci observed after DEN initiation, in clear contrast to PB. The results thus demonstrated that harman and norharman are nontoxic for the liver and lack modifying potential for liver carcinogenesis in our medium-term bioassay system.