Abstract
A single oral administration of orthophenylphenol (OPP, 1400 mg/kg; about half the LD50) to male Fischer 344 rats produced an elevation of serum transaminase activity 24 h later. Pretreatment with l-buthionine-S,R-sulfoximine (BSO, 900 mg/kg) in the OPP-treated rats potentiated the hepatic and renal damage which was accompanied by necrosis. Six hours after the administration of OPP (700 or 1400 mg/kg), hepatic and renal glutathione (GSH) levels decreased with increasing dosage. Hepatic GSH depletion with OPP was enhanced with BSO pretreatment and the recovery of GSH in both organs was slow in the high-dose OPP group. These results suggest that hepatic and renal damage is associated with a serious and prolonged GSH depletion. When either phenyl-p-benzoquinone (PBQ) or phenylhydroquinone (PHQ), which are intermediates of OPP, was administered orally to rats at 700 or 1400 mg/kg, the mortality with the high dose of PBQ was 75% at 24 h. The serum transaminase activity and UN level increased with the low dose of PBQ, accompanied by necrotic hepatocytes. The toxic effects of PHQ on kidney or liver were less than those on PBQ. These observations suggest that the liver and kidney may be target organs for toxic actions of a large dose of OPP and its intermediate, PBQ.
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References
Drew R, Miners JO (1984) The effects of buthionine sulphoximine (BSO) on glutathione depletion and xenobiotic biotransformation. Biochem Pharmacol 33: 2989–2994
Ernst W (1965) Conversion and excretion of 2-hydroxydiphenyl in the rat. Arzneim Forsch 15: 632–636
Epstein M, Berk DP, Hollenberg NK, Adams F, Chalmers TC, Abrams HL, Marill JP (1970) Renal failure in the patient with cirrhosis. The role of active vasoconstriction. Am J Med 49: 175
Fawcett JK, Scott JE (1960) A rapid and precise method for the determination of urea. J Clin Pathol 13: 156–159
Griffith OW (1982) Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis. J Biol Chem 257: 13704–13712
Hiraga K, Fujii T (1981) Induction of tumors of the urinary system in F344 rats by dietary administration of sodium o-phenylphenate. Food Cosmet Toxciol 19: 303–310
Hodge HC, Maynard EA, Blanchet HJ, Spencer HC, Rowe VK (1952) Toxicological studies of orthophenylphenol (Dowicidel). J Pharmacol Exp Ther 104: 202–214
Kalf GF (1987) Recent advances in the metabolism and toxicity of benzene. CRC Crit Rev Toxicol 18: 141–159
Karmen A (1955) A note on the spectrophotometric assay of glutamic-oxalacetic transaminase in human blood serum. J Clin Invest 34: 131–133
Kaneda M, Teramoto S, Shingu A, Shirasu Y (1978) Teratogenicity and dominant-lethal studies with o-phenylphenol. J Pest Sci 3: 365–370
Kew MC, Brunt PR, Varma R, Honringan J, Williams HS, Sherlock S (1971) Renal and intrarenal blood flow in cirrhosis of the liver. Lancet ii: 504
Kew MC, Limbrick C, Varma R, Sherlock S (1972) Renal and intrarenal blood flow in non-cirrhotic portal hypertension. Gut 13: 763
Luster M, Dean JH, Boorman GA, Archer DL, Lauer L, Lawson LD, Moore JA, Wilson RE (1981) The effects of orthophenylphenol, Tris(2,3-dichloropropyl)phosphate, and cyclophosphamide on the immune system and host susceptibility of mice following subchronic exposure. Toxicol Appl Pharmacol 58: 252–261
Mannervick B (1982) Mercaptans. In: Jakoby WB, Caldwell J (eds) Metabolic basis of detoxification. Academic Press Inc, New York, pp 185–206
Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther 187: 185–194
Nakagawa Y, Tayama K, Nakao T, Hiraga K (1984) On the mechanism of butylated hydroxytoluene-induced hepatic toxicity in rats. Biochem Pharmacol 33: 2669–2674
Nakao T, Ushiyama K, Kbashima J, Nagai F, Nakagawa A, Ohno T, Ichikawa H, Kobayashi H, Hiraga K (1983) The metabolic profile of sodium o-phenylphenol after subchronic oral administration to rats. Food Chem Toxicol 21: 325–329
Ogata A, Ando H, Kubo Y, Hiraga K (1978) Teratological test of o-phenylphenol (OPP) and sodium o-phenylphenol (OPP-Na) in mice. Ann Rep Tokyo Metro Res Lab Public Health 29-2: 89–96
Reitz RH, Fox TR, Quast JF, Hermann Ea, Watanabe PG (1983) Molecular mechanisms involved in the toxicity of orthophenylphenol and its sodium salt. Chem-Biol Interact 43: 99–119
Reitz RH, Fox TR, Quast JF, Hermann EA, Watanabe PG (1984) Biochemical factors involved in the effects of orthophenylphenol (OPP) and sodium orthophenylphenol (SOPP) on the urinary tract of male F344 rats. Toxicol Appl Pharmacol 73: 345–349
Robenek H, Meiss R, Themann H, Himmels S (1980) A correlated thin-section and freeze-fracture study of o-phenylphenol-induced alterations in the rat liver. Exp Cell Biol 48: 404–420
Shirasu Y, Moriya M, Kato K, Tezuka H, Henmi R, Shingu A, Kaneda M, Teramoto S (1978) Mutagenicity testing on o-phenylphenol Mutat Res 54: 227
Suzuki H, Suzuki N, Sasaki M, Hiraga K (1985) Orthophenylphenol mutagenicity in human cell strain. Mutat Res 156: 123–127
Taniguchi N, Tsukada Y, Hirai H (1974) Acquirement of fetal properties in hepatoma on glutathione metabolism. Biochim Biophys Acta 354: 161–167
Tayama K, Iguchi S, Hiraga K (1980) Acute oral toxicity of o-phenylphenol (OPP) in rats. Ann Rep Tokyo Metro Res Lab Public Health 31-2: 1–6
Tayama-Nawai S, Yoshida S, Nakao T, Hiraga K (1984) Induction of chromosome aberrations and sister-chromatid exchanges in CHO-K1 cells by o-phenylphenol. Mutat Res 141: 95–99
Wanger HU, Gompper R (1974) Quinone methides. In: Patai S (ed) The chemistry of the quinoid compounds. John Wiley & Sons, London, pp 1145–1178
Webb JL (1966) Effects on various metabolic systems. In: Webb JL (ed) Enzymes and enzyme inhibitors. Academic Press, New York, pp 493–594
Zimmerman HJ (1982) Chemical hepatic injury and its detection. In: Plaa G, Hewitt WR (eds) Toxicology of liver. Raven Press, New York, pp 1–45
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Part of this work was presented at IInd International ISSX Meeting “Xenobiotic Metabolism and Disposition”, May 16–20, 1988, Kobe, Japan
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Nakagawa, Y., Tayama, K. Effect of buthionine sulfoximine on orthophenylphenol-induced hepato- and nephrotoxic potential in male rats. Arch Toxicol 62, 452–457 (1988). https://doi.org/10.1007/BF00288349
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DOI: https://doi.org/10.1007/BF00288349