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Archives of Toxicology

, Volume 82, Issue 6, pp 343–353 | Cite as

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

  • Jiunn-Jye Chuu
  • Zih-Ning Huang
  • Hsun-Hsin Yu
  • Liang-Hao Chang
  • Shoei-Yn Lin-Shiau
Inorganic Compounds

Abstract

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 Ca2+-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.

Keywords

Hypnosis HgS Cinnabar ATPase Nitric oxide 

Notes

Acknowledgments

This investigation was supported by a research grant (CCMP88-RD-045) Committee on Chinese pharmacy, Department of Health, Executive Yuan, Taipei, Taiwan and a research grant (NSC-94-2-2320-B-002-010 and NSC 93-2320-B-002-045) from National Science Council, Taipei, Taiwan.

References

  1. Alexidis AN, Rekka EA, Kourounakis PN (1994) Influence of mercury and cadmium intoxication on hepatic microsomal CYP2E and CYP3A subfamilies. Res Commun Mol Pathol Pharmacol 85(1):67–72PubMedGoogle Scholar
  2. Anjum F, Shakoori AR (1994) Sublethal effects of inorganic mercury on the bodygrowth rate and liver function enzymes of phenobarbitone-pretreated and promethazine-pretreated rabbits. J Environ Pathol Toxicol Oncol 13(2):125–132PubMedGoogle Scholar
  3. Annau Z (1987) The use of pharmacological challenges in behavioral toxicology. Zentralbl Bakteriol Mikrobiol Hyg B 185(1–2):61–64PubMedGoogle Scholar
  4. Aschner M, Clarkson TW (1988) Distribution of mercury 203 in pregnant rats and their fetuses following systemic infusions with thiol-containing amino acids and glutathione during late gestation. Teratology 38(2):145–155PubMedCrossRefGoogle Scholar
  5. Aschner M, Clarkson TW (1987) Mercury 203 distribution in pregnant andnonpregnant rats following systemic infusions with thiol-containing amino acids. Teratology 36(3):321–328PubMedCrossRefGoogle Scholar
  6. Birke G, Johnels AG, Plantin LO, Sjostrand B, Skerfving S, Westermark T (1972) Studies on humans exposed to methyl mercury through fish consumption. Arch Environ Health 25:77–91PubMedGoogle Scholar
  7. Boldyrev AA, Bulygina ER, Kramarenko GG, Vanin AF (1997) Effect of nitroso compounds on Na+/K+-ATPase. Biochim Biophy Acta 1321:243–251CrossRefGoogle Scholar
  8. Cali JJ, Ma D, Sobol M, Simpson DJ, Frackman S, Good TD, Daily WJ, Liu D. (2006) Luminogenic cytochrome P450 assays. Expert Opin Drug Metab Toxicol Aug; 2(4):629–645CrossRefGoogle Scholar
  9. Cember H (1969) A model for the kinetics of mercury elimination. Am Ind Hyg Assoc J 30:367–371PubMedGoogle Scholar
  10. Chakrabarti SK (1981) Influence of mercury of the anesthetic response to and of distribution thiopental in rats. J Toxicol Env Health 7:765–774CrossRefGoogle Scholar
  11. Chen Y, Ferguson SS, Negishi M, Goldstein JA (2004) Induction of human CYP2C9 by rifampicin, hyperforin, and phenobarbital is mediated by the pregnane X receptor. J Pharmacol Exper Ther 308:495–501CrossRefGoogle Scholar
  12. Chuu JJ, Hsu CJ, Lin-Shiau SY (2001b) Abnormal auditory brainstem responses for mice treated with mercurial compounds: involvement of excessive nitric oxide. Toxicology 162(1):11–22PubMedCrossRefGoogle Scholar
  13. Chuu JJ, Liu SH, Lin-Shiau SY (2001c) Effects of methyl mercury, mercuric sulfide and cinnabar on active avoidance responses, Na+/K+-ATPase activities and tissue mercury contents in rats. Proc Natl Sci Counc Repub China B 25(2):128–136PubMedGoogle Scholar
  14. Daly AK (2003) Pharmacogenetics of the major polymorphic metabolizing enzymes. Fundam Clin Pharmacol 17(1):27–41 (Review)PubMedCrossRefGoogle Scholar
  15. Eto K (2006) Minamata disease: a neuropathological viewpoint. Seishin Shinkeigaku Zasshi 108(1):10–23 (Review)PubMedGoogle Scholar
  16. Fernandez-Martinez R, Rucandio MI (2005) Study of the suitability of HNO3 and HCl as extracting agents of mercury species in soils from cinnabar mines. Anal Bioanal Chem 381(8):1499–1506PubMedCrossRefGoogle Scholar
  17. Foley TD, Rhoads DE (1994) Stimulation of synaptosomal Na+, K(+)-ATPase by ethanol: possible involvement of an isozyme-specific inhibitor of Na+, K(+)-ATPase. Brain Res 653:167–172PubMedCrossRefGoogle Scholar
  18. Goldsmith RH, Soares JH Jr (1975) Barbiturate potentiation in mercury poisoning. Bull Environ Contam Toxicol 13(6):737–740PubMedCrossRefGoogle Scholar
  19. Guillaume D, Grisar T, Delgado Escueta AV (1986) Phenytoin dephosphorylates the catalytic subunit of the Na+/K+-ATPase in C57 BL mice. J Neurochem 47:904–911PubMedCrossRefGoogle Scholar
  20. Hardy AD, Sutherland HH, Vaishnav R, Worthing MA (1995) A report on the composition of mercurials used in traditional medicines in Oman. J Ethnopharmacol 49(1):17–22PubMedCrossRefGoogle Scholar
  21. Ho BS, Lin JL, Huang CC, Tsai YH, Lin MC (2003) Mercury vapor inhalation from Chinese red (Cinnabar). J Toxicol Clin Toxico 41(1):75–78CrossRefGoogle Scholar
  22. Iverson F, Downie RH, Trenholm HL, Paul C (1974) Accumulation and tissue distribution of mercury in the guinea pig during subacute administration of methyl mercury. Toxicol Appl Pharm 27:60–69CrossRefGoogle Scholar
  23. Iwakawa S, Miyashita K, Hashimoto Y, Kuroda T (2006) Effect of glimepiride and glibenclamide on S-warfarin 7-hydroxylation by human liver microsomes, recombinant human CYP2C9.1 and CYP2C9.3. Biol Pharm Bull 29(9):1983–1985PubMedCrossRefGoogle Scholar
  24. Kadiyska M, Stoytchev T (1979) Influence of the acute intoxication with salts of some heavy metals on hexobarbital sleep and hexobarbital metabolism. Acta Physiol Pharmacol Bulg 5(4):35–43PubMedGoogle Scholar
  25. Kaliman PA, Nikitchenko IV, Barannik TV, Sokol OA (1999) Metabolism of heme and hemoproteins in rat liver upon administration of mercuric chloride. Ukr Biokhim Zh 71(6):81–85PubMedGoogle Scholar
  26. Kawalek JC, Howard KD, Farrell DE, Derr J, Cope CV, Jackson JD, Myers MJ (2003) Effect of oral administration of low doses of pentobarbital on the induction of cytochrome P450 isoforms and cytochrome P450-mediated reactions in immature Beagles. Am J Vet Res 64(9):1167–1175PubMedCrossRefGoogle Scholar
  27. Kim CY, Nakai K, Kameo S, Kurokawa N, Liu ZM, Satoh H (2000) Protective effect of melatonin on methylmercury-induced mortality in mice. Tohoku J Exp Med 191(4):241–246PubMedCrossRefGoogle Scholar
  28. Knobeloch L, Steenport D, Schrank C, Anderson H (2006) Methylmercury exposure in wisconsin: a case study series. Environ Res 101(1):113–22PubMedCrossRefGoogle Scholar
  29. Kuznetsov DA, Zavijalov NV, Govorkov AV, Sibileva TM (1987) Methyl mercury-induced nonselective blocking of phosphorylation processes as a possible cause of protein synthesis inhibition in vitro and in vivo. Toxicol Lett 36(2):153–160PubMedCrossRefGoogle Scholar
  30. Larrey D, Pageaux GP (1997) Genetic predisposition to drug-induced hepatotoxicity. J Hepatol 26(Suppl 2):12–21 (Review)PubMedCrossRefGoogle Scholar
  31. Lee JH, Han DH (1995) Maternal and fetal toxicity of methylmercuric chloride administered to pregnant Fischer 344 rats. J Toxicol Environ Health 45(4):415–425PubMedGoogle Scholar
  32. Liang AH, Xu YJ, Shang MF (2005) Analysis of adverse effects of cinnabar. Zhongguo Zhong Yao Za Zhi 30(23):1809–1811PubMedGoogle Scholar
  33. Lin CH, Kang BH, Wong CH, Mao SH, Wan FJ (1999) Systemic administration of d-amphetamine induced a delayed production of nitric oxide in the straitum of rats. Neurosci Lett 276:141–144PubMedCrossRefGoogle Scholar
  34. Liu SH, Sheu ZJ, Lin RH, Lin Shiau SY (1997) The in vivo effect of lipopoly-saccharide on neuromuscular transmission in the mouse. Eur J Pharmacol 333:241–247PubMedCrossRefGoogle Scholar
  35. Loredo J, Alvarez R, Ordonez A (2005) Release of toxic metals and metalloids from Los Rueldos mercury mine (Asturias, Spain). Sci Total Environ 340(1–3):247–260PubMedGoogle Scholar
  36. Masubuchi Y, Hosokawa S, Horie T, Suzuki T, Ohmori S, Kitada M, Narimatsu S (1994) Cytochrome P450 isozymes involved in propranolol metabolism in human liver microsomes. The role of CYP2D6 as ring-hydroxylase and CYP1A2 as N-desisopropylase. Drug Metab Dispos 22(6):909–915PubMedGoogle Scholar
  37. Nabeshima T, Ho IK (1981) Pharmacological responses to pentobarbital in different strains of mice. J Pharmacol Exp Ther J216(1):198–204Google Scholar
  38. Park TM (1994) Abnormal cortical unit activity of the reticular formation. Electromyo Clin Neurophysiol 34:427–435Google Scholar
  39. Pokk P, Sepp E, Vassiljev V, Vali M (2001) The effects of the nitric oxide synthase inhibitor 7-nitroindazole on the behaviour of mice after chronic ethanol administration. Alcohol Alcohol 36(3):193–198PubMedGoogle Scholar
  40. Raucy JL, Mueller L, Duan K, Allen SW, Strom S, Lasker JM (2002) Expression and induction of CYP2C P450 enzymes in primary cultures of human hepatocytes. J Pharmacol Exp Ther 302(2):475–482PubMedCrossRefGoogle Scholar
  41. Rohn TT, Hinds TR, Vincenzi FF (1993) Ion transport ATPases as targets for free radical damage. Protection by an aminosteroid of the Ca2+ pump ATPase and Na+/K+ pump ATPase of human red blood cell membranes. Biochem Pharmacol 46:525–534PubMedCrossRefGoogle Scholar
  42. Sahi J, Stern RH, Milad MA, Rose KA, Gibson G, Zheng X, Stilgenbauer L, Sadagopan N, Jolley S, Gilbert D, LeCluyse EL (2004) Effects of avasimibe on cytochrome P450 2C9 expression in vitro and in vivo. Drug Metab Dispos 32(12):1370–1376PubMedCrossRefGoogle Scholar
  43. Sano K, Shimojo N, Yamaguchi S (1990) Effects of methylmercury on ethanol induced sleeping time of mice. Nippon Eiseigaku Zasshi 45(2):717–722PubMedGoogle Scholar
  44. Saper RB, Kales SN, Paquin J, Burns MJ, Eisenberg DM, Davis RB, Phillips RS (2004) Heavy metal content of ayurvedic herbal medicine products. JAMA 292(23):2868–2873PubMedCrossRefGoogle Scholar
  45. Sato Y, Seo N, Kobahashi E (2005) The dosing-time dependent effects of intravenous hypnotics in mice. Anesth Analg 101(6):1706–1708PubMedCrossRefGoogle Scholar
  46. Schoof RA, Nielsen JB (1997) Evaluation of methods for assessing the oral bioavailability of inorganic mercury in soil. Risk Anal 17:545–555 (Review)PubMedCrossRefGoogle Scholar
  47. Shinyashiki M, Kumagai Y, Nakajima H, Nagafune J, Homma Takeda S, Sagai M, Shimojo N (1998) Differential changes in rat brain nitric oxide synthase in vivo and in vitro by methylmercury. Brain Res 798:147–155PubMedCrossRefGoogle Scholar
  48. Stoytchev T, Krotev L (1978) Effect of subacute intoxication with some heavy metals on hexobarbital sleep and metabolism. Acta Physiol Pharmacol Bulg 4(3):29–35PubMedGoogle Scholar
  49. Strolin Benedetti M, Whomsley R, Baltes E (2006) Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics. Expert Opin Drug Metab Toxicol 2(6):895–921 (Review)PubMedCrossRefGoogle Scholar
  50. Su MQ, Okita GT (1986) Effects of methylmercury on hypnotic action of hexobarbital, liver hydroxylase and cytochrome P-450 in mice. Toxicology 39(3):233–245PubMedCrossRefGoogle Scholar
  51. Suzuki H, Kneller MB, Rock DA, Jones JP, Trager WF, Rettie AE (2004) Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors. Arch Biochem Biophys 429(1):1–15PubMedCrossRefGoogle Scholar
  52. Talarek S, Fidecka S (2004) Involvement of nitricoxidergic system in thehypnotic effects of benzodiazepines in mice. Pol J Pharmacol 56(6):719–726PubMedGoogle Scholar
  53. Talarek S, Fidecka S (2002) Role of nitric oxide in benzodiazepines-induced antinociception in mice. Pol J Pharmacol J54(1):27–34Google Scholar
  54. Testa B, Kramer SD (2007) The biochemistry of drug metabolism—an introduction: part 2. Redox reactions and their enzymes. Chem Biodivers 4(3):257–405 ReviewPubMedCrossRefGoogle Scholar
  55. Tonner PH, Scholz J, Schlamp N, Schulteam Esch J (1999) Inhibition of nitric oxide metabolism enhances the hypnotic-anesthetic action of the alpha2-adrenoceptor agonist dexmedetomidine in vivo. J Neurosurg Anesth 11:37–41Google Scholar
  56. Trasande L, Landrigan PJ, Schechter C (2006) Public health and economic consequences of methyl mercury toxicity to the developing brain. Environ Health Perspect 113(5):590–596CrossRefGoogle Scholar
  57. Vezer T, Papp A, Kurunczi A, Parducz A, Naray M, Nagymajtenyi L (2005) Behavioral and neurotoxic effects seen during and after subchronic exposure of rats to organic mercury. Environ Toxicol Pharmacol 19:785–796CrossRefGoogle Scholar
  58. Wang JH, Ye ZG, Liang AH, Xue BY, Wang YS, Wang ZM, Wang L, Li CY, Zhang J, Huang N, Jin AY (2003) Absorption and distribution of mercury and arsenic from realgar and cinnabar of angong niuhuang pill in normal rats and rats with cerebral ischemia. Zhongguo Zhong Yao Za Zhi 28(7):639–642PubMedGoogle Scholar
  59. Wang WH, Yu ZH, Cai M, Xu XM, Wu GP (1990) Antifertility actions of gossypol derivatives and analogues. Acta Pharmacologica Sinica. 11(3):268–271PubMedGoogle Scholar
  60. Weaver RJ, Thompson S, Smith G, Dickins M, Elcombe CR, Mayer RT, Burke MD (1994) A comparative study of constitutive and induced alkoxyresorufin O-dealkylation and individual cytochrome P450 forms in cynomolgus monkey (Macaca fascicularis), human, mouse, rat and hamster liver microsomes. Biochem Pharmacol 47(5):763–773PubMedCrossRefGoogle Scholar
  61. Wild LG, Ortega HG, Lopez M, Salvaggio JE (1997) Immune system alteration in the rat after indirect exposure to methyl mercury chloride or methyl mercury sulfide. Environ Res 74:34–42PubMedCrossRefGoogle Scholar
  62. Yamada M, Minami T, Yamada G, Tohno Y, Tohno S, Ikeda Y, Tashiro T, Kohno Y, Kawakami K (1997) Different element ratios of red cosmetics excavated from ancient burials of Japan. Sci Total Environ 199(3):293–298PubMedCrossRefGoogle Scholar
  63. Yamamoto I (1985) Studies on the behavior of mercury and selenium in blood of mice injected with those elements. Hokkaido Igaku Zasshi 60(2):227–240PubMedGoogle Scholar
  64. Yamamoto I, Ho IK (1978) Sensitivity to continuous administration of pentobarbital in different strains of mice. Res Commun Chem Pathol Pharmacol 19(3):381–388PubMedGoogle Scholar
  65. Ye ZG, Wang JH, Liang AH, Xue BY, Wang YS, Wang ZM, Wang L, Li CY, Zhang J, Huang N, Jin AY (2003) Comparative studies on pharmacological effects of angong niuhuang pill with its simplified prescription. Zhongguo Zhong Yao Za Zhi 28(7):636–639PubMedGoogle Scholar
  66. Yen CC, Liu SH, Chen WK, Lin RH, Lin-Shiau SY (2002) Tissue distribution of different mercurial compounds analyzed by the improved FI-CVAAS. J Anal Toxicol 26(5):286–295PubMedGoogle Scholar
  67. Yeoh TS, Lee AS, Lee HS (1986) Absorption of mercuric sulphide following oral administration in mice. Toxicology 41:107–111PubMedCrossRefGoogle Scholar
  68. Young YH, Chuu JJ, Liu SH, Lin-Shiau SY (2002) Neurotoxic mechanism of cinnabar and mercuric sulfide on the vestibulo-ocular reflex system of guinea pigs. Toxicol Sci 67(2):256–263PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Jiunn-Jye Chuu
    • 1
  • Zih-Ning Huang
    • 1
  • Hsun-Hsin Yu
    • 1
  • Liang-Hao Chang
    • 1
  • Shoei-Yn Lin-Shiau
    • 2
  1. 1.Institute of BiotechnologyCollege of Engineering, Southern Taiwan UniversityTainanTaiwan
  2. 2. Institute of Pharmacology College of Medicine, National Taiwan UniversityTaipeiTaiwan, ROC

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