Dilek BAYRAM, Meral ÖNCÜ, Efkan UZ, Haci Ramazan YILMAZ, Ayşe YİĞİT, Ahmet KOÇAK

The effects of midazolam and etomidate on the antioxidant system in the rat liver

This study was conducted to investigate the histopathological and biochemical effects of midazolam and etomidate, which are intravenous anesthetics used in surgical operations, on rat liver. There were 3 study groups each consisting of 9 animals: the control, midazolam, and etomidate groups. Midazolam and etomidate were administered 10 times with 1-day intervals. At the end of the study, tissues were taken for histological examination and biochemical analysis. We determined superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels in the liver. There was a slight increase in MDA level in the midazolam-exposed group when compared with the controls, and this was not statistically significant. However, SOD and CAT activities were significantly increased in the midazolam group. We found slight damage in histological sections in parallel to biological findings. MDA levels were significantly increased in the etomidate group and SOD and CAT activities were also prominent in this group. More histological changes like hepatocyte degeneration, vascular congestion, and mononuclear cell infiltration were observed in the etomidate group and this was statistically significant. We can say that these intravenous anesthetic agents may cause dose-dependent damage in tissue. Therefore, we think that one must be cautious of the administration duration and dose levels of anesthetics during surgical operations.

Anahtar Kelimeler:

Catalase, etomidate, liver, malondialdehyde, midazolam, superoxide dismutase

The effects of midazolam and etomidate on the antioxidant system in the rat liver

Keywords:

Catalase, etomidate, liver, malondialdehyde, midazolam, superoxide dismutase,

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Abdel-Wahhab MA, Nada SA, Arbid MS (1999). Ochratoxicosis: prevention of developmental toxicity by L-methionine in rats. J Appl Toxicol 19: 7–12.
Abidova SS (2002). The effects of propofol and ketamine on the lipid metabolism and peroxidation in rats. Eksp Klin Farmakol 65: 46–48.
Aebi Y (1984). Catalase in vitro. Method Enzymol 105: 121–126.
Aitkenhead AR, Smith G, editors (1990). Intravenous Anesthetic Agents. Textbook of Anesthesia. 2nd ed. Edinburgh, UK: Churchill Livingstone.
Amrein R, Hetzel W (1990). Pharmacology of dormicum (midazolam) and anexate (flumazenil). Acta Anaesth Scand 92: 6–15.
Atiba JO, Horai Y, White PF, Trevor AJ, Blaschke TF, Sung ML (1988). Effect of etomidate on hepatic drug metabolism in humans. Anesthesiology 68: 920–924.
Bachowski S, Kolaja KL, Xu Y, Ketcham CA, Stevenson DE, Walborg EF Jr, Klaunig JE (1997). Role of oxidative stress in the mechanism of dieldrin’s hepatotoxicity. Ann Clin Lab Sci 27: 196–208.
Bleecker J, Lison D, Abeele KV, Willems J, Reuck J (1994). Acute and subacute organophosphate poisoning in rat. Neurotoxicology 15: 341–348.
Bushnell PJ, Kelly KL, Ward TR (1994). Repeated inhibition of cholinesterase by chlorpyrifos in rats: behavioral, neurochemical and pharmacological indices of tolerance. J Pharmacol Exp Ther 270: 15–25.
Ceylan BG, Nazıroğlu M, Uğuz AC, Barak C, Erdem B, Yavuz L (2011). Effects of vitamin C and E combination on element and oxidative stress levels in the blood of operative patients under desflurane anesthesia. Biol Trace Elem Res 141: 16–25.
Codogan JIG (1973). Principles of Free Radical Chemistry. London, UK: The Chemical Society.
Correia LM, Bonilha DQ, Gomes GF, Brito JR, Nakao FS, Lenz L, Rohr MR, Ferrari AP, Libera ED (2011). Sedation during upper GI endoscopy in cirrhotic outpatients: a randomized, controlled trial comparing propofol and fentanyl with midazolam and fentanyl. Gastrointest Endosc 73: 45–51.
Drapper HH, Hadley M (1990). Malondialdehyde determination as index of lipid peroxidation. Method Enzymol 186: 421–431.
Emoto C, Iwasaki K (2007). Relative roles of CYP2C19 and CYP3A4/5 in midazolam 1’-hydroxylation. Xenobiotica 37: 592–603.
Fassoulaki A, Andreopoulou K, Williams G, Pateras C (1986). The effect of single and repeated doses of thiopentone and fentanyl on liver function in the rat. Anaesth Intens Care 14: 145–147.
Fatmi W, Kechrid Z, Nazıroğlu M, Flores-Arce M (2013). Selenium supplementation modulates zinc levels and antioxidant values in blood and tissues of diabetic rats fed zinc-deficient diet. Biol Trace Elem Res 152: 243–250.
Fee JPH, McCaugghey W, Clarke RSJ, Wallace WFM (1997). Sedative drugs. In: Anaesthetic Physiology and Pharmacology. New York, NY, USA: Churchill Livingston, pp. 191–206.
Gillman AG, Rall TW, Nies AS, Taylor P (1991). Goodman & Gillman’s The Pharmacological Basis of Therapeutics. 8th ed. New York, NY, USA: McGraw-Hill.
Hanquet M (1972). Manuel d’Anesthesiologie. Paris, France: Masson et Cie (in French).
Hoen PA, Bijsterbosch MK, van Berkel TJ, Vermeulen NP, Commandeur JN (2001). Midazolam is a phenobarbital-like cytochrome P450 inducer in rats. J Pharmacol Exp Ther 299: 921–927.
Horai Y, White PF, Trevor AJ (1985). The effect of etomidate on rabbit liver microsomal drug metabolism in vitro. Drug Metab Dispos 13: 364–367.
Işık G (2004). Intravenöz Anestezikler. Adana, Turkey: Çukurova Üniversitesi Tip Fakültesi Anesteziyoloji Ders Notları (in Turkish).
Jabor VA, Coelho EB, Dos Santos NA, Bonato PS, Lanchote VL (2005). A highly sensitive LC-MS-MS assay for analysis of midazolam and its major metabolite in human plasma: applications to drug metabolism. J Chromatogr B 822: 27–32.
Jong RH, Bonin JD (1981). Benzodiazepines protect mice from local anesthetic convulsions and deaths. Anesth Analg 60: 385–389. Khanderia U, Pandit SK (1987). Use of midazolam hydrochloride in anesthesia. Clinical Pharmacy 7: 533–547.
Kobayaski Y, Ishigame Y, Usui T (1977). Superoxide dismutase activity of human granulocytes and lymphocytes. Lancet 6: 865–866.
Koçkar MC, Nazıroğlu M, Çelik Ö, Tola HT, Bayram D, Koyu A (2010). N-acetylcysteine modulates doxorubicin-induced oxidative stress and antioxidant vitamin concentrations in liver of rats. Cell Biochem Funct 28: 673–677.
Krumholz W, Weidenbush H, Menges T, Keller G, Hempelmann G (2001). The influence of intravenous anesthetics on the activity of enzymes released from polymorphonuclear leukocytes. Eur J Anaesth 18: 151–158.
Lee JH, Kim D, Hong HN, Han SM, Kim JU (2000). Protective effect of etomidate on kainic acid-induced neurotoxicity in rat hippocampus. Neurosci Lett 286: 179–182.
Lichtenstein D, Jagannath S, Baron T, Anderson MA, Banerjee S, Dominitz JA, Fanelli RD, Gan SI, Harrison ME, Ikenberry SO et al. (2008). Sedation and anesthesia in GI endoscopy. Gastrointest Endosc 68: 815–826.
Liu FZ, Zhang WS, Luo CZ (2009). Effect of etomidate on mitochondrial energy metabolism of rat livers in vitro. Sichuan Da Xue Xue Bao Yi Xue Ban 40: 529–532.
Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ (1951). Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275.
Lunec J, Blake D (1990). Oxygen free radicals: their relevance to disease processes. In: Cohen RD, Lewis B, Albert KGMM, editors. The Metabolic and Molecular Basis of Acquired Disease. London, UK: Balliere Tindall, pp. 189–212.
Molina-Hernandez M, Tellez-Alcantara NP (2001). Estrus variation in anticonflict effects of midazolam microinjected into septal nuclei in female Wistar rats. Pharmacol Biochem Behav 68: 531–537.
Murphy PG, Bennett JR, Myers DS, Davies MJ, Jones JG (1993). The effect of propofol anesthesia on free radical-induced lipid peroxidation in the rat liver. Eur J Anaesth 10: 261–266.
Nazıroğlu M (2012). Molecular role of catalase on oxidative stressinduced Ca2+ signaling and TRP cation channel activation in nervous system. J Recept Signal Transduct Res 32: 134–141.
Nazıroğlu M, Karaoğlu A, Aksoy AO (2004). Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats. Toxicology 195: 221–230.
Nilsson A (1991). Benzodiazepines and their reversal. In: Kay B, editor. Monographs in Anesthesiology: Total Intravenous Anesthesia. 21st ed. Amsterdam, the Netherlands: Elsevier, pp. 57–80.
Niwa Y, Ishimato K, Kanoh T (1990). Induction of superoxide dismutase in leukocytes by paraquat: correlation with age and possible predictor of longevity. Blood 76: 835–841.
Okutomi T, Nomto K, Nakamura K, Goto F (1995). Autogenous production of hydroxyl radicals from thiopental. Acta Anaesthesiol Scand 39: 338–342.
Özcan O, Karaöz E, Sarsılmaz M, Ozan H, Sınav A, Oba G (1992). Sıçanlarda karbontetraklorür hepatotoksisitesine karşı E vitaminin etkisi. Doğa Dergisi 16: 45–54 (in Turkish).
Rang HP, Dale MM, Ritter JM, Gardner P (1995). Pharmacology. 3rd ed. New York, NY, USA: Churchill Livingstone.
Reves JG, Flezzani P, Kissin I (1987). Pharmacology of anesthetic induction drugs. In: Kaplan SA, editor. Cardiac Anesthesia. 2nd ed. Orlando, FL, USA: Grune and Stratton Inc., pp. 466– 469.
Reves JG, Glass PSA, Lubarsky DA (1999). Nonbarbiturate intravenous anesthetics. In: Miller RD, editor. Anesthesia. 5th ed. New York, NY, USA: Churchill Livingstone, pp. 228–272.
Riphaus A, Wehrmann T, Weber B, Arnold J, Beilenhoff U, Bitter H, von Delius S, Domagk D, Ehlers AF, Faiss S et al (2009). S3 Guideline: sedation for gastrointestinal endoscopy 2008. Endoscopy 41: 797–915.
Sear JW (1987). Toxicity of intravenous anaesthetics. Brit J Anaesth 59: 24–45.
Sun Y, Oberley LW, Ying L (1988). A simple method for clinical assay of superoxide dismutase. Clin Chem 34: 497–500.
Trevor AJ, Miller RD (1998). General anesthetics. In: Katzung BG, editor. Basic and Clinical Pharmacology. 7th ed. New York, NY, USA: Lange Medical, pp. 409–423.
Vinik HR, Reves JG, Nixon D (1981). Midazolam induction and emergence in renal failure patients. Anesthesiology 55: 262.