Evaluation of hepatotoxicity potential of cinnabar-containing An-Gong-Niu-Huang Wan, a patent traditional Chinese medicine

An-Gong-Niu-Huang Wan (AGNH) is a patent traditional Chinese medicine for brain disorders. It contains 10% cinnabar (HgS). Hg is known to produce toxicity to the kidney, brain and liver. Is AGNH safe? Liver is a major organ for drug metabolism, whether the long-term use of AGNH would affect hepatic P450 enzymes is unknown. To address these concerns, mice were given orally cinnabar (300 mg/kg), cinnabar-containing AGNH daily for 44 days, and liver toxicity was examined and compared with that of methylmercury (MeHg, 2.6 mg/kg) and mercuric chloride (HgCl2, 32 mg/kg). Serum aminotransferases were increased by MeHg and HgCl2 only. Histopathology showed more severe liver damage in MeHg- and HgCl2-treated mice than in the cinnabar and AGNH groups. Accumulation of Hg in MeHg- and HgCl2-treated mice was 96- and 71-fold higher than controls, respectively, but was only 2-fold after cinnabar and AGNH administration. Expressions of metallothionein-1 and heme oxygenase-1, biomarkers for Hg toxicity, were increased by MeHg and HgCl2, but were not altered in cinnabar- and AGNH-treated mice. Expression of hepatic cytochrome P450 genes, such as Cyp1a1, Cyp1b1 and Cyp4a10 was increased only after MeHg and HgCl2, and the expressions of Cyp3a11and Cyp3a25 were increased by all treatments, indicating the potential Hg-drug interactions after long-term use of cinnabar-containing traditional medicines. Taken together, the results demonstrate that AGNH is much less hepatotoxic than common mercurials, and that the use of total Hg content to evaluate the toxicity of cinnabar-containing traditional Chinese medicines appears to be inappropriate.