TO THE MECHANISM OF SEASONAL VARIATIONS IN CARBON TETRACHLORIDE TOXICITY
Introduction. Seasonal biorhythms can modify the toxic effect of xenobiotics. Natural fluctuations in hormone levels in the blood which can modify the metabolic processes in the liver can be the base of one of the mechanisms in this phenomenon. The study of the effector role of testosterone in seasonal chrono-reactivity can reveal one new link in the pathogenesis and will improve health risk assessment, especially in patients taking hormone therapy. The aim of the study was to reveal the role of testosterone in the mechanisms of chrono-reactivity the toxic effect for carbon tetrachloride in warm-blooded animals. Material and Methods. Studies were conducted on adult male Wistar rats, divided into negative control groups, a model with CCl4-induced toxic hepatitis, and experimental in which CCl4 exposure was carried out following a preliminary 7-day course of testosterone administration. Direct and total bilirubin, cholesterol, alkaline phosphatase, AlAT and AsAT, hydroperoxide and malondialdehyde were determined by standard methods. The experiment was repeated twice: both in winter and spring. Results. The amplitude of the damage to the structures and functions of hepatocytes from a single injection of the same poison dosage in winter and spring manifested in varying degrees, revealing the modulatory role of biological rhythms. Under premedication with testosterone, a similar tendency was observed in both series of the experiment (winter, spring): the toxic effect of CCl4 increased. This was recorded by the following biochemical changes: bilirubin increased by 55%, cholesterol - 19%, alkaline phosphatase - 12%, AlAT - 17%, AsAT - 35%, hydroperoxide - 29%, and malonic dialdehyde slightly (relative to groups with model toxic hepatitis). Conclusion. The male sex hormone regulating the metabolic activation of cytochromes in hepatocytes performing biotransformation is one of the effector links in the seasonal chrono-reactivity phenomena. The discovery of the whole mechanism will allow developing an effective system of chronoprophylaxis and reducing the risks of toxic poisoning in individuals during periods of maximum chrono-reactivity.
About the authorsSkupnevskii Sergey V.
Soldin O.P., Chung S.H., Mattison D.R. Sex Differences in Drug Disposition. J Biomed Biotechnol. 2011; 2011: 187103. doi: 10.1155/2011/187103.
Skakun N.P., Ciljurik I.T., Volkova JI.A., Kudin A.T. Seasonal features of the liver excretory function by tetracycline damage and correction of disorders with antioxidants. Antibiotiki. 1983; 28 (10): 757-760. (in Russian)
Jakobson G.S., Dobrovol’skaja S.G., Vakula G.M. Effects of sex and phase of the estrous cycle on the intensity of damage and recovery processes in the rat liver after acute intoxication with carbon tetrachloride. Bjulleten’ jeksperimental’noj biologii i mediciny. 1978; 85 (4): 460-4. (in Russian)
Liu Y., Santillo M.F., Flynn T.J., Ferguson M.S. Sex hormone modulation of both induction and inhibition of CYP1A by genistein in HepG2/C3A cells. In Vitro Cell Dev Biol Anim. 2015; 51 (4): 426-431. doi: 10.1007/s11626-014-9848-9.
Arushanjan E.B. Chronopharmacology. Stavropol’: SGMA, 2000. (in Russian)
Skakun N.P., Vysockij I.Ju. Seasonal features of tetracycline hepatotoxicity. Antibiotiki. 1984; 29 (1): 42-5. (in Russian)
Seawright A.A., Steele D.P., Menrath R.E. Seasonal Variations in Hepatic Microsomal Oxidative Metabolism in vitro and Susceptibility to Carbon Tetrachloride in a Flock Sheep. Australian Veterinary Journal. 1972; 48: 488-94.
Wolfe G.W., Schnell R.C. Annual Differences in Daily Variations in Hepatic Drug Metabolizing Enzyme Activity and Plasma Hormone Levels in Rat. Pharmacology. 1979; 19: 116-20.
Chibisov S.M., Rapoport S.I., Blagonravov M.L., red. Chronobiology and chronomedicine. M.: RUDN, 2018. (in Russian)
Rapoport S.I., Frolov V.A., Hetagurova L.G., red. Chronobiology and chronomedicine: The manual. M.: OOO «Med. inf. agentstvo», 2012. (in Russian)
Komarov F.I., red. Chronobiology and chronomedicine. M.: Medicina, 1989. (in Russian)
Zemljanova M.A., Pustovalova O.V., Mazunina D.L, Sboev A.S. Biochemical indicators of negative effects in children with exposure of organochlorine compounds in drinking water. Gigiena i Sanitaria [Hygiene and Sanitation, Russian journal]. 2006; 95 (1): 97-101. (in Russian)
Zemlyanova M.A., Karpova M.V., Novosyolov V.G. Assessment of genome stability in children with long-term exposure to carbon tetrachloride in drinking water. Zdorov’e naselenija i sreda obitanija. 2015; 273 (12): 36-41. (in Russian)
Toxicological profile for carbon tetrachloride. U.S. Department of Health and Human Services. Public Health Service. Agency for Toxic Substances and Disease Registry, 2005.
Clawson G.A. Mechanisms of carbon tetrachloride hepatotoxicity. Pathol Immunopathol Res. 1989; 8 (2): 104-12.
McGregor D., Lang M. Carbon tetrachloride: genetic effects and other modes of action. Mutat Res. 1996; 366 (3): 181-95.
Burcham Ph.C. An Introduction to Toxicology. Springer Science & Business Media, 2014.
Nwidu L.L., Oboma Y.I., Elmorsy E., Carter W.G. Alleviation of carbon tetrachloride-induced hepatocellular damage and oxidative stress with a leaf extract of Glyphae brevis (Tiliaceae). J Basic Clin Physiol Pharmacol. 2018; 29 (6): 609-19. doi: 10.1515/jbcpp-2017-0058.
Khabriev R.U., ed. The manual for experimental (preclinical) study of new pharmacological substances. M.: OJSC «Izdatel’stvo «Medicina», 2005. (in Russian). (in Russian)
Giannini E.G., Testa R., Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ. 2005; 172 (3): 367-79. doi: 10.1503/cmaj.1040752.
Kamel H.H., Sarhan R.M., Saad Gh.A. Biochemical assessment of oxidative status versus liver enzymes in patients with chronic fascioliasis. J Parasit Dis. 2015; 39 (4): 628-33. doi: 10.1007/s12639-014-0431-9.
Flynn T.J., Ferguson M.S. An in vitro system for studying potential biological mechanisms of human sex differences in susceptibility to acute liver injury. Toxicol Lett. 2010; 198 (2): 232-6. doi: 10.1016/j.toxlet.2010.07.003.
Lee V.W.K., De Kretser D.M, Hudson B., Wang C. Variations in serum FSH, LH and testosterone levels in male rats from birth to sexual maturity. J Reprod Fert. 1975; (42): 121-6.
Weber L.W., Boll M., Stampf A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 2003; 33 (2): 105-36. DOI: 10.1080/713611034.
Schradin C. Seasonal changes in testosterone and corticosterone levels in four social classes of a desert dwelling sociable rodent. Hormones and Behavior. 2008; 53: 573-9.
Parks R.M., Bennett J.E., Foreman K.J., Toumi R., Ezzati M. National and regional seasonal dynamics of all-cause and cause-specific mortality in the USA from 1980 to 2016. eLife. 2018; 7: e35500. doi: 10.7554/eLife.35500.
- Refbacks are not listed
Контент доступен под лицензией Creative Commons Attribution 3.0 License.