Attenuation by methyl mercury and mercuric sulfide of pentobarbital induced hypnotic tolerance in mice through inhibition of ATPase activities and nitric oxide production in cerebral cortex

• Published in: Archives of toxicology 2008-06, Vol.82 (6), p.343-353
• Main Authors: Chuu, Jiunn-Jye, Huang, Zih-Ning, Yu, Hsun-Hsin, Chang, Liang-Hao, Lin-Shiau, Shoei-Yn
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - metabolism; Administration, Oral; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Calcium-Transporting ATPases - antagonists & inhibitors; Calcium-Transporting ATPases - metabolism; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Chemical and industrial products toxicology. Toxic occupational diseases; Cytochrome P-450 Enzyme System - metabolism; Disease Models, Animal; Drug Synergism; Drug Tolerance; Environmental Health; Enzymes; Hypnosis; Hypnotics and Sedatives - pharmacology; Inorganic Compounds; Liver - drug effects; Liver - enzymology; Male; Medical sciences; Mercury; Mercury Compounds - pharmacokinetics; Mercury Compounds - toxicity; Metals and various inorganic compounds; Methylmercury Compounds - pharmacokinetics; Methylmercury Compounds - toxicity; Mice; Neurology; Nitric oxide; Nitric Oxide - metabolism; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Phenobarbital - pharmacology; Rodents; Sleep - drug effects; Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors; Sodium-Potassium-Exchanging ATPase - metabolism; Toxicology
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-007-0255-9

This study is aimed at exploring the possible mechanism of hypnosis-enhancing effect of HgS or cinnabar (a traditional Chinese medicine containing more than 95% HgS) in mice treated with pentobarbital. We also examined whether the effect of HgS is different from that of the well-known methyl mercury (MeHg). After a short period (7 days) of oral administration to mice, a nontoxic dose (0.1 g/kg) of HgS not only significantly enhanced pentobarbital-induced hypnosis but also attenuated tolerance induction; while a higher dose (1 g/kg) of HgS or cinnabar exerted an almost irreversible enhancing effect on pentobarbital-hypnosis similar to that of MeHg (2 mg/kg) tested, which was still effective even after 10 or 35 days cessation of administration. To study comparatively the effects of different mercury forms from oral administration of MeHg and HgS on membrane ATPase activities of experimental mice, analysis of the Hg content in the cerebral cortex revealed that correlated with the decrease of Na + /K + -ATPase and Ca 2+ -ATPase activities. Furthermore, NO levels of blood but not that of cerebral cortex were also decreased by mercuric compounds. Although pentobarbital alone enhanced cytochrome p450–2C9 in time dependent manner, all of mercurial compounds tested had no such effect. All of these findings indicated that the mercurial compounds including cinnabar, HgS and MeHg exert a long-lasting enhancing hypnotic activity without affecting pentobarbital metabolism, which provides evidence-based sedative effect of cinnabar used in Chinese traditional medicine for more than 2,000 years. The nontoxic HgS dosing (0.1 g/kg/day) for consecutive 7 days is perhaps useful for delaying or preventing pentobarbital-tolerance.