Previous studies by our group demonstrated that radix Sophorae tonkinensis could induce hepatotoxicity. However, it remains unclear which components of this herb may be responsible for its hepatotoxicity. The present study aimed to investigate the hepatic toxicity of treatment with matrine (MT) and oxymatrine (OMT) alone or simultaneously. Furthermore, the current study aimed to identify whether the hepatotoxicity induced by OMT is actually the toxic characterization of its metabolite MT. Hepatotoxicity was evaluated by biochemical and histopathological approaches in subchronic toxicity in mice, as well as via evaluation of cytotoxicity and enzyme leakage in AML12 liver cells. The results indicated that treatment of mice with OMT and MT individually or simultaneously resulted in centrilobular hypertrophy in the liver at doses equivalent to that contained in radix S. tonkinensis at a hepatotoxic dose, suggesting that MT and OMT are likely hepatotoxic components of this herb. OMT-induced hepatotoxicity may be primarily exerted via its metabolite MT in mice. Furthermore, OMT combined with MT was observed to be more toxic compared with OMT or MT alone. These results extend our understanding of the hepatotoxicity of radix S. tonkinensis and its active ingredients.

Abstract:In the present survey, the historical data for spontaneous tumors observed in our laboratory was compared in relation to the time-related changes between recent (2000)(2001)(2002)(2003)(2004) and past (1990-1999) samples from Fischer 344 rats used in carcinogenicity studies. In the recent samples, there were statistically increased incidences of islet cell adenomas in males and uterine adenocarcinomas in females. On the other hand, there were decreased incidences of pheochromocytomas, prostatic adenomas, pituitary anterior adenomas, large granular lymphocytic (LGL) leukemias and Leydig cell tumors in males and pituitary anterior adenomas in females. Furthermore, there were decreases in the body weights of both sexes at 58 weeks of age in the recent samples, and this may have been related to the decreases in the incidences of pheochromocytomas, Leydig cell tumors, prostatic adenomas and LGL leukemias. Moreover, the decreased incidence of pheochromocytoma in males revealed a positive correlation with a decreased percentage of severe chronic progressive nephropathy (CPN). On the other hand, there were no distinct factors responsible for increased incidences of tumors observed in the recent samples, suggesting a possible genetic drift. In conclusion, the incidences of spontaneous tumors obtained in our laboratory have been changed with time. Smaller body weights in both sexes and reduction in the number of male cases with severe CPN might be related to the reduced incidence of certain types of tumors in recent animals. (J Toxicol Pathol 2008; 21: 53-60)

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Busulfan is an antineoplastic bifunctional alkylating agent. We previously reported the busulfan-induced systemic histopathological changes in fetal rats and the sequence of brain lesions in fetal and infant rats. In the present study, in order to clarify the nature and sequence of busulfan-induced systemic histopathological changes in infant rats, 6-day-old male infant rats were subcutaneously administered 20 mg/kg of busulfan and histopathologically examined at 1, 2, 4, 7 and 14 days after treatment (DAT). As a result, histopathological changes characterized by pyknosis of component cells were observed in the heart, lungs, stomach, intestines, liver, kidneys, testes, epididymides, hematopoietic and lymphoid tissues, dorsal skin and femur as well as in the brain and eyes (data not shown in this paper). Such pyknosis transiently appeared until 7 DAT with prominence at 2 and/or 4 DAT in each tissue, except for the thymus, in which pyknosis peaked at 1 DAT. Most of the pyknotic nuclei were immunohistochemically positive for cleaved caspase-3, indicating that pyknotic cells were apoptotic. Different from the reports of fetal and adult rats, apoptosis was also found in cardiomyocytes and osteoblasts in infant rats.

Busulfan, an antineoplastic bifunctional-alkylating agent, is known to induce developmental anomalies. In the present study, we examined the distribution and sequence of pyknotic cells in rat fetal tissues exposed to busulfan. Pregnant rats on gestation day 13 were administered intraperitoneally 30 mg/kg of busulfan, and fetal tissues were examined at 6, 12, 24, 36, 48, 72 and 96 hours after treatment (HAT). Pyknosis of component cells was observed markedly in the brain, moderately in the eyes and spinal cord and mildly in the craniofacial tissue, mandible, limb buds, tail bud, ganglions, alimentary tract, lungs, kidneys, pancreas and liver. In the brain, mitotic inhibition was also detected. Most of the pyknotic cells were considered to be apoptotic cells judging from the results of TUNEL staining and electron microscopic examination. Commonly in the above-mentioned tissues, pyknotic cells began to increase at 24 HAT, peaked at 36 or 48 HAT and disappeared at 96 HAT, which is when the histological picture returned to normal in most tissues except for the brain, spinal cord and eyes. The present study clarified the outline of busulfan-induced apoptosis in rat fetuses.