METALLOTHIONEIN (MT)-NULL MICE ARE SENSITIVE TO CISPLATIN-INDUCED HEPATOTOXICITY

cis-Diamminedichloroplatinum (cisplatin) is an important anticancer dr ug used to treat solid tumors. The nephrotoxicity of cisplatin is reco gnized as the most important dose-limiting factor, but high doses of c isplatin also produce hepatotoxicity. However, little is known about c isplatin-induced liver injury and the role of metallothionein, a cyste ine-rich, metal-binding protein, in modulating its hepatotoxicity. Thi s study was designed to examine cisplatin hepatotoxicity in control an d metallothionein-I/II knockout (MT-null) mice. Animals were given a s ingle injection of cisplatin (50-200 mu mol/kg ip), and liver injury w as evaluated 3-16 h later. Cisplatin produced dose-and time-dependent liver injury, as evidenced by increased serum activity of alanine amin otransferase (ALT), as well as by histopathology. Apoptosis, rather th an necrosis, predominates in cisplatin-induced liver injury, as indica ted by increased numbers of apoptotic cells (hematoxylin and eosin sta ining), in situ apoptotic DNA detection, and DNA fragmentation on agar ose gel electrophoresis. MT-null mice were more sensitive than control s to cisplatin-induced hepatotoxicity. Cisplatin (200 mu mol/kg) was l ethal to 124 of control mice, but 60% of MT-null mice died within 16 h . At the dose of 150 mu mol/kg, serum ALT activities were increased 2- fold in control mice compared to 6.5-fold in MT-null mice. Apoptotic l esions were more pronounced in MT-null than in control mice. MT-null m ice were also more susceptible than controls to cisplatin-induced neph rotoxicity, as evidenced by having higher blood urea nitrogen concentr ations. Furthermore, cultured MT-null hepatocytes were more sensitive than control cells to the cytotoxicity of cisplatin (50-200 mu M), as indicated by lactate dehydrogenase leakage into the medium. These resu lts demonstrate that (1) high doses of cisplatin produce hepatotoxicit y, with apoptosis as the major lesion, and (2) MT protects against cis platin-induced liver injury. (C) 1998 Academic Press.