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

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.

Molecular mechanisms of tirapazamine (SR 4233, Win 59075)-induced hepatocyte toxicity under low oxygen concentrations

“…This generates a free radical which may exert its cytotoxic effects through DNA single-and double-strand breaks, probably as a result of hydrogen abstraction, but not by direct binding to DNA (Baker et al, 1988;Laderoute et al, 1988;Costa et al, 1989). The centrilobular location of the hepatic necrosis induced by tirapazamine in rats (White et al, 1992) could therefore be explained by the low oxygen concentration in this liver zone (Kessler et al, 1973). Cytochrome P450 2E1 is also located in the centrilobular zone of the liver (Anundi et al, 1993) and would be more reductive at low oxygen concentrations.…”

“…It is also an effective anti-tumour agent in vivo in combination with radiation or compounds which enhance tumour hypoxia (Brown, 1987). However subcapsular necrosis of the liver, necrosis of the kidney medulla and olfactory epithelium and bone marrow toxicity have been reported in rats after acute dosing with tirapazamine at 0.3 mmol kg ' (White et al, 1992). Liver necrosis was confined to hepatocytes of the centrilobular zone (zone 3) which normally experience low oxygen tensions of 1-3% (White et al, 1992).…”

“…However subcapsular necrosis of the liver, necrosis of the kidney medulla and olfactory epithelium and bone marrow toxicity have been reported in rats after acute dosing with tirapazamine at 0.3 mmol kg ' (White et al, 1992). Liver necrosis was confined to hepatocytes of the centrilobular zone (zone 3) which normally experience low oxygen tensions of 1-3% (White et al, 1992). Recently, it has been confirmed that the toxicity of tirapazamine to Chinese hamster fibroblasts does not level off at high oxygen concentrations but continues to decrease as the oxygen concentrations increases (Koch, 1993).…”

Comparative Acute Systemic Toxicity of Several Quinoxaline 1,4-Di-N-oxides in Wistar Rats

“…The acute i.p. toxicity of several benzotriazine 1,4 di-N-oxides has been reported as being in a range between 0.06 and 1.3 mmol/kg in Balb/c mice, and approximately 0.33 mmol/kg for tirapazamine in rats [42,36]. Therefore, the range of toxicity of the compounds studied is similar to benzotriazine 1,4 di-N-oxides and lower than other reduced quinoxalines.…”

“…The intraperitoneal acute toxicity study was carried out following the strategy of the up-and-down method, with some modifications [35]. The starting dose of 60 mg/kg was chosen based on the LD 50 for the tirapazamine [36]. This dose was administered to three animals and depending on the results, a higher dose of 120 mg/kg or a lower dose of 30 mg/kg, was given to another group of three animals.…”