Summary
The modulatory potential of noscapine, an opium alkaloid was assessed on the ethanol-induced changes in hepatic drug metabolizing enzyme systems, glutathione content and microsomal lipid peroxidation. Noscapine was administered orally to male Wistar rats at a dose level of 200 mg/kg bw alone as well as in combination with 50% ethanol (v/v) for 5 days. Noscapine administration was associated with a ∼91% decrease in hepatic microsomal cytochrome P-450 content. A decline of ∼36% was observed in the NADPH-cytochrome c reductase activity on noscapine administration. The lowering of cytochrome P-450 levels on noscapine administration was accompanied by a concomitant increase in heme oxygenase activity as well as serum bilirubin levels. Our results indicate that the combination dosage of noscapine and ethanol antagonised the ethanol-induced elevation of cytochrome P-450 levels. Noscapine fed rats had decreased glutathione (GSH) content and enhanced lipid peroxidation compared to control rats as indexed by MDA method. Further, noscapine and ethanol coexposure produced a more pronounced elevation in lipid peroxidation and the glutathione levels also decreased significantly. We speculate on the basis of our results that the significant enhancement of lipid peroxidation on combination dosage of noscapine and ethanol is a consequence of depletion of glutathione to certain critical levels. The inhibition of glutathione-S-transferase (GST) as well as lowering of cytochrome P-450 suggests that the biotransformation of noscapine and ethanol is significantly altered following acute coexposures.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Tanaka T. and Misawa S., (2000): Cytochrome P450 2E1: its clinical and toxicological role, J. Clin. Pharm & Therap., 25, 3, 165–175.
Tanaka E. and Misawa S., (1998): Pharmacokinetic interactions between acute alcohol ingestion and single doses of benzodiazepines and tricyclic and tetracyclic antidepressants-an update, J. Clin. Pharm & Therap., 23(5), 331–336.
Williams, R.T (1971): Handbook of Experimental Pharmacology, 28, pp 226–249, Springer Verlag, Berlin.
Singh, A., Singh, Prakash S. and Bamezia, R (1997): Modulatory influence of arecoline on the phytic acid-altered hepatic biotransformation system enzymes sulfhydryl content and lipid peroxidation in a murine system. Cancer Letters, 117, 1–6.
Ye, Keqiang, Ke, Yong, Keshava, N., Shanks, J., Kapp, J.A., Tekmal, R.R., Petros, J., and Joshi, H.C (1998): Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells, Proc. Natl. Acad. Sci., USA, 95, 1601–1606.
Ke, Y., Ye, K. et al (2000): Noscapine inhibits tumor growth with little toxicity to normal tissues or inhibition of immune responses, Cancer Immunol Immunother, 49, 217–225.
Zhou, J., Gupta K., Aggarwal, S., Aneja, R., Chandra, R., Panda, D. and Joshi, H.C. (2003): Brominated derivatives of noscapine are potent microtubule interfering agents that perturb mitosis and inhibit cell proliferation, Mol. Pharmacol, 63, 1–9.
Omura, T. and Sato, R. (1964): The carbon-monoxide binding pigment of liver microsomes, J. Biol. Chem, 239, 7, 2370–2378.
Christensen, F and Wissing F: NADPH cytochrome c reductase (1972): inhibition of microsomal drug metabolizing enzymes from rat liver by various 4-hydroxy coumarin derivatives, Biochem. Pharmacol, 21, 975.
Habig, W.H., Pabst, M.J. and Jokoby, W.B: Gluthione S-transferase (1974): The first enzymatic step in mercapturic acid formation, J. Biol. Chem., 249, 7130–7139.
Jollow, D.J., Mitchell, J.R., Zampaglione, N. and Gillete J.R (1974): Bromobenzene induced liver necrosis: Protective role of glutathione and evidence for 3,4-bromobenzeoxide as a hepatotoxic intermediate, Pharmacology, 11, 151–169.
Wright, D.J., Colby, H.D and Miles P.R. (1981): Cytosolic factors which affect microsomal lipid peroxidation in lung and liver, Arch. Biochem. and Biophy. 206, 296–304.
Malloy, H.T. and Evelyn, K.A (1937): The determination of bilirubin with the photoelectric colorimeter, J. Biol. Chem., 19, 984–993.
Maines, M.D (1975): Cobalt stimulation of heme degradation in the liver Dissociation of microsomal oxidation of heme cytochrome P-450, J. Biol. Chem. 250, 4171–4177.
Lowry, O.H, Rosenbrough, N.J., Farr, A. L., and Randall, R.J. (1951): Protein measurement with Folin phenol reagent, J. Biol. Chem., 193, 265–275.
Fabbizzewski, R., Chewiecko, M., Holownia, A., and Paolowska, P. (1991): The decrease of superoxide dismutase activity and depletion of sulfhydryl compound in ethanol induced liver injury, Drug Ethanol Depend, 28, 291–294.
Chandra, R. and Aneja, R., (1998): Cytochrome P-450 Enzymes: Significance, multiplicity of isoforms, substrates, catalytic and regulatory mechanism, physiological functions and clinical correlations, J. Ind. Chem. Soc, 75, 795–803.
Pirmohamed M, Park BK, (2003): Cytochrome P450 enzyme polymorphisms and adverse drug reactions. Toxicology, 192(1), 23–32.
Lin, H., Lu, A. et al (2001): Interindividual variability in inhibition and induction of cytochrome P450 enzymes, Annu. Rev. Pharmacol. Toxicol., 41, 535–567.
Nebert, D.W. and Negishi, M (1982): Multiple forms of cytochrome P450 and the importance of molecular biology and evaluation. Biochem. Pharmacol., 31, 2311–2317.
Conney, A.H. (1982): Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons, Cancer Research, 42, 4875–4917.
Upreti, K.K., Das, Mukul, Khanna, S.K (1991): Biochemical toxicology of argemone oil, effect on hepatic cytochrome P450 and xenobiotic on drug metabolizing enzymes. J. Appl. Toxicol., 11(3), 203–209.
Wills, E.D (1971): Effect of lipid peroxidation on membrane-bound enzymes of the endoplasmic reticulum, Biochem J., 123, 933–941.
Levine, W.G (1982): Glutathione, lipid peroxidation and regulation of cytochrome P-450 activity, Life Sci., 31, 779–784.
Vatsis, K.P., Kowalchyk, J.A. and Schulman, M.P (1974): Ethanol and drug metabolism in mouse liver microsomes subsequent to lipid peroxidation- induced destruction of cytochrome P-450, Biochem. Biophys. Res. Commun., 61, 1.
Ashakumary, L., and Vijayammal, P.L (1996): Additive effect of ethanol and nicotine on lipid peroxidation and antioxidant defense mechanisms in rats, J. Appl. Toxicol, 1(4), 305–308.
Orrenius, S. and Moldeus, P. (1984): The multiple roles of glutathione in drug metabolism, Trends in Pharmacol Sci, 5, 432–435.
Anundi, I., Hobberg, J., and Stead, A.H (1979): Glutathione depletion in isolated hepatocytes: its relation to lipid peroxidation and cell damage, Acta Pharmacol. Toxicol., 45, 45–51.
Younes, M. and Siegers, C.P (1980): Lipid peroxidation as a consequence of glutathione depletion in rat and mouse liver. Res. Commun. Chem. Pathol. Pharmacol, 27, 119–128.
Jokoby, W.B (1977): The Glutathione-S-transfereases. A group of multifunctional detoxification proteins, Adv. Enzymol., 46, 383–414.
Harata, J., Nagata M., Sasaki, Fz., Ishigero, I., Ohta, Y. and Murakami, Y (1983): Effect of prolonged administration on activities of various enzymes scavenging activated oxygen radicals and lipid peroxide level in the liver of rats, Biochem. Pharmacol., 32, 1795–1798.
Toker, N.K., Vysal M., Aykac, G., Sivas, A., Yalcin, S., and Oz, H (1985): Influence of acute ethanol administration on hepatic glutathione peroxidase and glutathione transferase activities in the rat, Pharmacol. Res. Commun., 17, 233–239.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Aneja, R., Katyal, A. & Chandra, R. Modulatory influence of noscapine on the ethanol-altered hepatic biotransformation system enzymes, glutathione content and lipid peroxidation in vivo in rats. European Journal of Drug Metabolism and Pharmacokinetics 29, 157–162 (2004). https://doi.org/10.1007/BF03190592
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03190592