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Elevated Formation of Nitrate and N-Nitrosodimethylamine in Woodchucks (Marmota monax) Associated with Chronic Woodchuck Hepatitis Virus Infection¹

Institute of Comparative and Environmental Toxicology, Stocking Hall [R. H. L., J. H. H.], and College of Veterinary Medicine [B. B., B. C. T.], Cornell University, Ithaca, New York 14853

Nitrate balance and N-nitrosodimethylamine (NDMA) excretion were studied in woodchucks chronically infected with woodchuck hepatitis virus (WHV). Twenty-four-h urinary recovery of a bolus dose of [¹⁵N]nitrate was 54 ± 12% in woodchucks. WHV-infected animals formed 3-fold more nitrate endogenously than did control animals (P < 0.01). Treatment of WHV-infected animals with Escherichia coli lipopolysaccharide increased nitrate excretion 15-fold, while uninfected animals increased nitrate excretion 4-fold. The endogenous formation of NDMA was higher in WHV-infected woodchucks than in uninfected controls. After administration of L-[¹⁵N₂]arginine, [¹⁵N]nitrate, and [¹⁵N]NDMA were detected in urine indicating that arginine is a precursor of biosynthesized nitrate and the hepatocarcinogen NDMA. NDMA probably results from the formation of nitrosating agents during the oxidation of arginine to oxides of nitrogen and citrulline. Woodchucks chronically infected with WHV develop hepatocellular carcinomas with high frequency. Our observations suggest an additional mechanism that may be involved in the pathogenesis of hepatocellular carcinoma associated with chronic WHV infection.

¹ This research was supported in part by USPHS Grant CA-37264 to B. C. T.

² To whom requests for reprints should be addressed.

Received 3/13/91. Accepted 5/23/91.

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