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Acetone is a clear, colorless liquid that is highly flammable and infinitely soluble in water. Years of clinical study, laboratory testing, and practical experience have shown that acetone can be used safely and without harm in many industrial and commercial applications. The long‐standing interest in the biochemical, pharmacological, and toxicological properties of acetone can be traced to three important characteristics of the chemical: Acetone is a normal by‐product of mammalian metabolism; levels within the body can, however, be altered by changes in nutrition or energy balance. Acetone is a highly volatile organic solvent that is miscible with water; thus large amounts of the vapor can be absorbed through the lungs and quickly distributed throughout the body. Acetone is manufactured and used in large amounts in a variety of commercial and industrial applications; thus the potential for exogenous human exposure is widespread.
Acetone is a clear, colorless liquid that is highly flammable and infinitely soluble in water. Years of clinical study, laboratory testing, and practical experience have shown that acetone can be used safely and without harm in many industrial and commercial applications. The long‐standing interest in the biochemical, pharmacological, and toxicological properties of acetone can be traced to three important characteristics of the chemical: Acetone is a normal by‐product of mammalian metabolism; levels within the body can, however, be altered by changes in nutrition or energy balance. Acetone is a highly volatile organic solvent that is miscible with water; thus large amounts of the vapor can be absorbed through the lungs and quickly distributed throughout the body. Acetone is manufactured and used in large amounts in a variety of commercial and industrial applications; thus the potential for exogenous human exposure is widespread.
The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is nephrotoxic in rats. Previous studies have suggested that oxidative hepatic biotransformation is required for the induction of kidney damage. The experiments described in this paper were designed to further investigate the relationship between NDPS metabolism and nephrotoxicity using various modulators of cytochrome P450 activity. Male Fischer 344 rats were pretreated with the P450 inducers Aroclor 1254 (ARO), isoniazid (INH), 3-methylcholanthrene (3-MC), and phenobarbital (PB), or the P450 inhibitor 1-aminobenzotriazole (ABT). Control animals received vehicle only. NDPS metabolism was investigated using hepatocytes isolated from the various treatment groups. Separate experiments were also conducted to evaluate the effects of these pretreatments on NDPS-induced nephrotoxicity in rats. PB and ARO enhanced formation of the known nephrotoxic NDPS metabolites, N-(3,5-dichlorophenyl)-2-hydroxysuccinimide, N-(3,5-dichlorophenyl>2-hydroxysuccinamic acid, and iV-(3,5-dichlorophenyl)-3-hydroxysuccinamic acid, by the hepatocytes. In contrast, ABT inhibited formation of the nephrotoxic metabolites, whereas INH and 3-MC did not alter NDPS biotransformation. NDPS-induced renal damage was potentiated by pretreating the rats with PB or ARO and was attenuated by ABT. Compared with control animals, toxicity was unaffected by INH or 3-MC pretreatments. Thus, there was a correlation between pretreatments that induce P450-mediated NDPS metabolism and the effects that these compounds have on NDPS-induced nephrotoxicity. The data indicate that specific P450 isozymes metabolize NDPS to its hydroxylated products and suggest that these metabolites mediate the nephrotoxicity induced by NDPS. © 1997 Sodtty of To iV-(3,5-Dichlorophenyl)succinimide (NDPS, Fig.
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