Abstract
Hydrazine hepatotoxicity in vivo, as manifested by triglyceride accumulation, depletion of ATP and reduced glutathione (GSH) was shown to be dose related. The effect of pretreatment of rats with various inhibitors and inducers of cytochrome P450 on these dose-response relationships was investigated. Pretreatment with the inhibitor piperonyl butoxide increased triglyceride accumulation whereas pretreatment with the inducers phenobarbital and β-naphthoflavone (BNF) resulted in reduced triglyceride accumulation. Pretreatment with the inducers acetone and isoniazid also enhanced triglyceride accumulation. Only phenobarbital pretreatment also significantly reduced GSH and ATP depletion. A linear correlation was found between hepatic glutathione and ATP levels in non-pretreated animals given various doses of hydrazine. However, exponential relationships were found between hepatic triglycerides and both hepatic ATP and glutathione. The results suggest that i) the hepatotoxicity of hydrazine can be modulated by inducing or inhibiting particular isoenzymes of cytochrome P450, ii) ATP and GSH depletion may not be directly involved in the development of fatty liver.
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References
Blair IA, Mansilla Tinoca R, Brodie MJ, Clare RA, Dollery CT, Timbrell JA, Beever IA (1985) Plasma hydrazine concentrations in man after isoniazid and hydralazine administration. Hum Toxicol 4: 195–202
Burke MD, Thosmpson S, Elcombe CR, Halpert J, Haaparanta T, Mayer RT (1985) Ethoxy-, pentoxy- and benzyloxyphenoxazones and homologues: a series of substrates to distinguish between different induced cytochromes P450. Biochem Pharmacol 34: 3337–3345
Butler WM Jr, Maling HM, Horning MG, Brodie BB (1960) The direct determination of liver triglycerides. J Lipid Res, 2: 95–96
Caulcutt R, Boddy R (1983) Reproducibility (2) In: Caulcutt R, Boddy R (eds) Statistics for analytical chemists. Chapman and Hall, London and New York, pp 148–159
Clark DA, Leeder LG, Foulds EL, Trout DL (1970) Changes in lipids of rat liver after hydrazine injection. Biochem Pharmacol 19: 1743–1752
Delaney J, Timbrell JA (1994) Modulation of hydrazine toxicity in vitro using various inhibitors and inducers of cytochrome P450 2E1. Hum Exp Toxicol (in press)
Dianzani MU (1978) Biochemical aspects of fatty liver. In: Slater TF (ed) Biochemical Mechanisms of liver injury. Academic Press, London, pp 45–95
Dunnett CW (1964) New tables for multiple comparisons with a control. Biometrics 20: 482–492
Ellman GL (1959) Tissue sulphydryl groups. Arch Biochem Biophys 82: 70–77
Ghatineh S, Timbrell JA (1994) The biochemical effects and toxicity of hydrazine in cultured rat hepatocytes Toxicol In Vitro (in press)
Gold J (1987) Hydrazine sulphate: a current perspective. Nutr Cancer 9: 59–66
Hyland R, Gescher A, Thummel K, Schiller C, Jheeta P, Mynett K, Smith AW, Mraz J (1992) Metabolic oxidation and toxification of N-methylformamide catalysed by the cytochrome P450 isoenzyme CYP2E1. Mol Pharmacol 41: 259–266
Jenner AM, Timbrell JA (1990) Hydrazine metabolism in rat liver microsomes. Hum Exp Toxicol 9: 335–336
Johansson I, Ekstrom G, Scholte B, Puzycki D, Jornvall H, Ingelman-Sundberg M (1988) Ethanol-, fasting- and acetone inducible cytochromes P-450 in rat liver: regulation and characteristics of enzymes belonging to the IIB and IIE gene subfamilies. Biochemistry 27: 1925–1934
Kimball RF (1977) The mutagenicity of hydrazine and some of its derivatives. Mutat Res 39: 111–126
Koop DR (1986) Hydroxylation of p-nitrophenol by rabbit ethanol-inducible cyt P-450 isozyme 3a. Mol Pharmacol 29: 399–404
Koop DR, Tierney DJ (1990) Multiple mechanisms in the regulation of ethanol-inducible cytochrome P450IIE1. Bioessays 12: 429–435
Lemasters JJ, Hackenbrock CR (1978) Firefly luciferase assay for ATP production by mitochondria. In: Marlene A, Deluca S (eds) Methods in enzymology Vol. 57. Academic Press, New York, pp 36–50
Lindros KO, Cai Y, Penttila KE (1990) Role of ethanol-inducible cytochrome P45011E1 in carbon tetrachloride induced damage to centrilobular hepatocytes from ethanol-treated rats. Hepatology 12: 1092–1097
Lopez-Mendoza D, Villa-Trevino S (1971) Hydrazine-induced inhibition of amino acid incorporation into rat liver protein. Lab Invest 25: 68–72
Lorr NA, Miller KW, Chung HR, Yang, CS (1984) Potentiation of the hepatotoxicity of N-nitrosodimethylamine by fasting, diabetes, acetone andisopropanol. Toxicol Appl Pharmacol 73: 423–431
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin-phenol reagent. J Biol Chem 193: 265–275
Moloney SJ, Prough RA (1983) Biochemical toxicology of hydrazines. Rev Biochem Toxicol 5: 313–346
Nelson SD, Gordon WP (1982) Metabolic activation of hydrazines. In: Snyder R, Parke DV, Kocsis JJ, Jollow DJ, Gibson GG, Witmer CM (eds) Biological reactive intermediates II, part B: chemical mechanisms and biological effects. Plenum Press, New York and London, pp 971–981
Nada A, Noda H, Ohno K, Sendo T, Misaka A, Kanazawa Y, Isobe R, Hirata M (1985a) Spin trapping of a free radical intermediate formed during microsomal metabolism of hydrazine. Biochem Biophys Res Commun 133: 1086–1091
Noda A, Sendo T, Ohno K, Goto S, Noda H, Hsu K-Y (1985b) Effects of rifampicin and phenobarbital on the fate of isoniazid and hydrazine in rats. Toxicol Lett 25: 313–317
Omura T, Sato, R (1964) The carbon monoxide binding pigment of liver microsomes. J Biol Chem 239: 2370–2378
Preece NE, Ghatineh S, Timbrell JA (1990) The role of ATP depletion in hydrazine hepatotoxicity. Arch Toxicol 64: 49–53
Preece NE, Nicholson JK, Timbrell JA (1991) Identification of novel hydrazine metabolites by 15N-NMR. Biochem Pharmacol 41: 1319–1324
Reinke LA, Moyer MJ (1985) p-Nitrophenol hydroxylation: a microsomal oxidation which is highly inducible by ethanol. Drug Metab Dispos 13: 548–552
Reynolds BA, Thomas AA (1965) A colorimetric method for the determination of hydrazine and monomethylhydrazine in blood. Am Ind Hyg J 26: 527–530
Ronis MJ, Johansson I, Hultenby K, Lageraratz J, Glaumann H, Ingelman-Sundberg M (1991) Acetone-regulated synthesis and degradation of cytochrome P450IIE1 and cytochrome P450IIB1 in rat liver. Eur J Biochem 198: 383–389
Steinhoff D, Mohr U, Schmidt WM (1990) On the question of carcinogenic action of hydrazine—evaluation on the basis of new experimental results. Exp Pathol 39: 1–9
Timbrell JA, Harland SJ (1979) Identification and quantification of hydrazine in the urine of patients treated with hydralazine. Clin Pharmacol Ther 26: 81–88
Timbrell JA, Scales MD, Streeter AJ (1982) Studies on hydrazine hepatotoxicity 2: biochemical findings. J Toxicol Environ Health 10: 955–968
Yang CS, Brady JF, Hong J (1992) Dietary effects on cytochromes P450, xenobiotic metabolism and toxicity. FASEB J 6: 737–744
Yasukochi Y, Masters BSS (1976) Some properties of a detergent-solubilized NADPH-cytochrome c (cytochrome P450) reductase purified by biospecific affinity chromatography. J Biol Chem 251: 5337–5344
Zand R, Nelson SD, Slattery JT, Thummel KE, Kalhorn TF, Adams SP, Wright JM (1993) Inhibition and induction of cytochrome P4502E1-catalysed oxidation by isonazid in humans. Clin Pharmacol Therap 54: 142–149
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Jenner, A.M., Timbrell, J.A. Influence of inducers and inhibitors of cytochrome P450 on the hepatotoxicity of hydrazine in vivo. Arch Toxicol 68, 349–357 (1994). https://doi.org/10.1007/s002040050081
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DOI: https://doi.org/10.1007/s002040050081