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.
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.
White
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MRC Toxicology Unit, Carshalton, Surrey, UK.
Cahill
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Davies
A
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Carthew
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P
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003579:Cytochrome Reductases / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008466:Mechlorethamine / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009928:Organ Specificity; D010084:Oxidation-Reduction; D011838:Radiation-Sensitizing Agents / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D000077704:Tirapazamine; D014227:Triazines / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*
D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D008466:Mechlorethamine; D003577:Cytochrome P-450 Enzyme System; D003579:Cytochrome Reductases