Abstract
Pathological lesions to male Fischer rats were investigated 24 h after the administration of 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) or nitromin, two compounds which need to undergo bioreductive activation in order to exert their toxic effects. Although SR 4233 reduction leads to a putative free radical species while with nitromin a bifunctional alkylating agent is formed, in both instances, the bone marrow was a major target organ. However, the response of other organs to these compounds differed. SR 4233 caused lesions to the olfactory epithelium, liver, kidney and thymus. Nitromin caused focal haemorrhages on the intestine, which were reduced in germ-free rats. Rates of reduction of SR 4233 or nitromin were determined under anaerobic conditions using microsomal preparations from target tissues. With SR 4233 as a substrate, reductase activities were highest in the olfactory epithelium, 6 fold higher than in the liver. SR 4233 reductase activities generally correlated with those of NADPH: cytochrome c reductase or the concentration of cytochrome P-450 reductase protein in the affected organs while with nitromin, there appeared to be no such relationship. The present results support the concept that the expression of pathological damage in vivo is a multifactorial process and does not directly correlate with initial rates of reduction of either drug determined in vitro.
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References
Aiko I, Owari S, Torigoe M (1952) Nitrogen mustard N-oxide and: effects on the Yoshida sarcoma. J Pharm Soc (Japan) 72: 1297–13
Bogdanffy MS (1990) Biotransformation enzymes in the rodent nas mucosa: the value of a histochemical approach. Environ Health Perspect 85: 177–186
Cahill A, White INH (1990) Reductive metabolism of 3-amino-1,2-benzotriazine-1,4-dioxide (SR 4233) and the induction of unscheduled DNA synthesis in rat and human derived cell lines. Carc nogenesis 11: 1407–1411
Costa AK, Baker MA, Brown JM, Trudell JR (1989) In vitro hepatotos icity of SR 4233 (3-amino 1,2,4-benzotriazine-1,4-dioxide), a hy poxic cytotoxin and potential antitumor agent. Cancer Res 925–929
Harlow E, Lane D (1988) Antibodies, a laboratory manual. Cold Sprit. Harbor Laboratory, p 505
Kessler M, Lang H, Sinagowitz E, Rink R, Hoper J (1973) Homeostas of oxygen supply in liver and kidney. In: Bruley DF, Bicher HI (eds Oxygen transport to tissue. Plenum Press, New York, pp 351–360
Laderoute K, Wardman P, Rauth AM (1988) Molecular mechanisms from the hypoxia dependent activation of 3-amino-1,2,4-benzotriazine 1,4-dioxide (SR 4233). Biochem Pharmacol 37: 1487–1495
Lake BG (1987) Preparation and characterisation of microsomal frac tions for studies on xenobiotic metabolism. In: Snell K, Mullock (eds) Biochemical toxicology: a practical approach. IRL Press, Ox ford, pp 183–215
Levene RD, Ibrahim NG (1982) The bone marrow as a metabolic organ Am Med J 73: 615–618
Lown JW (1979) The molecular mechanism of antitumor action of the mitomycins. In: Carter SK, Crooke ST (eds) Mitomycin c: current status and new developments. Academic Press, New York, pp 5–27
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein med surement with the folin phenol reagent. J Biol Chem 193: 265–275
Reed CJ, Lock EA, De Matteis F (1986) NADPH: cytochrome P-45 reductase in olfactory epithelium. Biochem J 240: 585–592
Safirstein R, Moel WD, Dikman S, Guttenplan J (1987) Cisplatin nephrotoxicity: insights into mechanism. Int J Androl 10: 325–346
Sartorelli AC (1988) Therapeutic attack of hypoxic cells of solid tumors presidential address. Cancer Res 48: 775–778
Scheline RR (1973) Metabolism of foreign compounds by gastrointesti nal microorganisms. Pharmacol Rev 25: 451–530
Voigt JM, Guengerich FP, Baron J (1985) Localization of a cytochrome P-450 isozyme (cytochrome P-450 PB-B) and NADPH-cytochrome P-450 reductase in rat nasal mucosa. Cancer Lett 27: 241–247
Walton MI, Workman P (1990) Enzymology of the reductive bioactivation of SR 4233. Biochem Pharmacol 39: 1735–1742
White INH, Suzangar M, Mattocks AR, Bailey E, Farmer PB, Connors TA (1989) Reduction of nitromin to nitrogen mustard: unschedulec DNA synthesis in aerobic or anaerobic rat hepatocytes, JB1, BL8 and Walker carcinoma cell lines. Carcinogenesis 10: 2113–2118
Yasukochi Y, Masters BSS (1976) Some properties of a detergent solubilised NADPH cytochrome c reductase (cytochrome P-450) reductase purified by biospecific affinity chromatography. J Biol Chem 251: 5337–5344
Zeman EM, Brown JM, Lemmon MJ, Hirst VK, Lee WW (1986 SR 4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells. Int J Radiat Oncol Biol Phys 12: 1239–1242
Zeman EM, Baker MA, Lemmon MJ, Pearson BA, Adams JA, Brown JM, Lee WW, Tracy M (1989) Structure-activity relationships for benzotriazine di-N-oxides. J Radiat Oncol Biol Phys 16: 977–981
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White, I.N.H., Cahill, A., Davies, A. et al. Acute lesions in rats caused by 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) or nitromin: a comparison with rates of reduction in microsomal systems from target organs. Arch Toxicol 66, 100–106 (1992). https://doi.org/10.1007/BF02342502
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DOI: https://doi.org/10.1007/BF02342502