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Enhancing Effects of Oltipraz on the Development of Spontaneous Hepatic Lesions in LEC Rats

Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan

Kazushi Okazaki

Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan

Akiyoshi Nishikawa

Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan, nishikaw{at}nihs.go.jp

Fumio Furukawa

Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan

Ken-Ichiro Kasahara

Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan

Makoto Miyauchi

Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan

Takayoshi Imazawa

Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan

Koji Uchida

Nagoya University Graduate School of Bioagricultural Sciences, Nagoya 464-8601, Japan

Masao Hirose

Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan

Oltipraz, developed as an antischistosomal agent, protects against the hepatotoxicity of many xenobiotics and is known to be an effective inhibitor of experimental carcinogenesi s in rodents. In the present study, we investigated its effects on the development of lesions in LEC rats, established as a mutant strain characterized by a hereditary predisposition for hepatic damage with severe jaundice. A total of 35 male 6-week-old LEC rats were divided into 2 groups, one administered diet supplemented with oltipraz at a dose of 400 ppm, and the other fed basal diet alone. Animals in each group were sequentially sacrificed at 10, 15, and 25 weeks after commencement of the oltipraz administration. Eight animals died or became moribund in the oltipraz group during weeks 10 and 11 of the treatment, whereas only one rat in the nontreatment group died after 16 weeks. All dead or moribund animals showed severe or moderate jaundice. The treatment caused a decrease in body weight gain from 9 to 13 weeks, and an increase in relative liver weight at each sacrifice point. Serum biochemical assays performed at week 25 revealed elevated levels of serum AST, ALT, LDH, ALP, -GTP, and Cu in the treated-animals. The glutathione level in the livers of oltipraz-treated animals was significantly higher than that in the control rats. Histopathologically, enlarged hepatocytes with large nuclei, focal necrosis, pigment granule-laden Kupffer cells and hypertrophy of renal tubule cells were observed in both groups, but the severity of these changes was greater in the oltipraz group. Our results thus indicate that spontaneous hepatic damage in LEC rats is enhanced by oltipraz, by a mechanism that remains to be elucidated.

Key Words: Oltipraz • LEC rat • hepatitis.

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