Metabolism and Disposition of [c]1-nitronaphthalene in Male Sprague- Dawley Rats

In rats and mice, 1-nitronaphthalene (1-NN) produces both lung and liver toxicity. Even though these toxicities have been reported, the metabolism and disposition of 1-NN have not been elucidated. Therefore, studies were performed to characterize its fate after i.p. and i.v. administration to male Sprague-Dawley rats. After i.p. administration of [C]1-NN (100 mg/kg; 60 mCi/kg), 84% of the dose was eliminated in the urine and feces by 48 h. At 96 h, 60% of the dose was recovered in the urine, 32% in the feces, and 1% collectively in the tissues, blood, and gastrointestinal contents. The terminal phase rate constant (kterm) of 1-NN was 0.21 h , the terminal phase half-life (T1/2,term) was 3.40 h, and the systemic bioavailability was 0.67. When administered i.v. (10 mg/kg; 120 mCi/kg), 85% of the dose was eliminated in the urine and feces by 24 h. At the end of the study (96 h), 56% of the dose was recovered in the urine, 36% in the feces, and 1% collectively in the tissues, blood, and gastrointestinal contents. Interestingly, 88% of the dose was secreted into bile by 8 h. The kterm was 0.94 h 21 and the T1/2,term was 0.77 h. The major urinary metabolite after both routes of administration was N-acetyl-S-(hydroxy-1-nitro-dihydronaphthalene)-Lcysteine. Other urinary metabolites identified include hydroxylated, dihydroxylated, glucuronidated, sulfated, and reduced metabolites, as well as dihydrodiol. The major biliary metabolite was hydroxyglutathionyl-1-nitro-dihydronaphthalene. These data show that 1-NN undergoes extensive metabolism and enterohepatic recirculation, and the majority of the dose is eliminated in the urine. 1-Nitronaphthalene (1-NN) has various commercial and industrial uses. It is used as a chemical intermediate in the production of dyes, a wood preservative, a fungicide, and a component in firework powder (Kasperczak and Lutomski, 1973; Dominik, 1978; Ying et al., 1986). 1-NN is an environmental contaminant in urban areas of the United States and Europe because of its presence in diesel engine exhaust in ambient airborne particulates (Nishioka et al., 1982; Ramdahl et al., 1982; Ramdahl and Urdal, 1982; Liberti et al., 1984; Brorstrom-Lunden and Lindskog, 1985; Draper, 1986). There is increasing concern about exposure to 1-NN and other nitroaromatics, particularly because Gupta et al. (1996) reported that these types of compounds in ambient air contributed to the mutagenic activity of respirable airborne particles. Rodent toxicity studies have shown that the major target organ for 1-NN-induced toxicity is the lungs. After a single i.p. injection, 1-NN causes a severe respiratory distress syndrome, acute loss of both ciliated and nonciliated cells, necrosis of the bronchiolar epithelium, and cytotoxicity to tracheal epithelium (Johnson et al., 1984; Paige et al., 1997). In vitro studies have shown that 1-NN is metabolized by cytochrome P-450 to a reactive metabolite(s) that binds to lung microsomes, lung slices, and isolated lung cells (Rasmussen, 1986; Price et al., 1995). With specific inhibitors of pulmonary cytochrome P-450 isoforms, Verschoyle and Dinsdale (1990) reported that cytochrome P-450 2B1 activity is correlated with 1-NN toxicity. Sauer et al. (1995) have shown that pulmonary toxicity is marked by infiltration of inflammatory cells into the interstitial areas around damaged bronchioles. Thus, the pulmonary toxicity caused by 1-NN administration to rats appears to involve both P-450-mediated bioactivation and a distinct inflammatory response. In addition to lung injury, hepatotoxicity also develops after 1-NN administration. Sauer et al. (1997) reported hepatocellular necrosis consisting of damage to the centrilobular and periportal hepatocytes, as well as bile duct epithelial cells. The hepatic toxicity induced by 1-NN is enhanced with phenobarbital pretreatment and diminished with SKF 525-A pretreatment, suggesting that cytochrome P-450 2B1 bioactivates 1-NN to reactive metabolites in the induced liver (John-