Received for publication May 12, 2005.
Revised July 27, 2005.
Accepted for publication July 28, 2005.

Metabolism of Myosmine in Wistar Rats

Abstract

The alkaloid myosmine is not only present in tobacco products but also in various foods. Myosmine is easily nitrosated yielding 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) and the esophageal tobacco carcinogen N'-nitrosonornicotine (NNN). Due to its widespread occurrence, investigations on the metabolism and activation of myosmine are needed for risk assessment. Therefore, the metabolism of myosmine has been studied in Wistar rats treated with single oral doses of [pyridine-5-³H]myosmine at 0.001, 0.005, 0.5 and 50 µmol/kg body weight. Oral administration was achieved by feeding a labeled apple bite. Radioactivity was completely recovered in urine and feces within 48 h. At the two lower doses, 0.001 and 0.005 µmol/kg, a higher percentage of the radioactivity was excreted in urine (86.2 ± 4.9% and 88.9 ± 1.7%) as compared to the higher doses, 0.5 and 50 µmol/kg, where only 77.8 ± 7.3% and 75.4 ± 6.6% of the dose was found in urine. Within 24 h urinary excretion of radioactivity was nearly complete with less than 4% of the total urinary output appearing between 24 and 48 h. The two major metabolites accounting for >70% of total radioactivity in urine were identified as 3-pyridylacetic acid (3-PAA, 20-26%) and 4-oxo-4-(3-pyridyl)butyric acid (keto acid, 50-63%) using UV-DAD detection and GC/MS measurements. 3-Pyridylmethanol (3-5%), 3'-hydroxymyosmine (2%) and HPB (1-3%) were detected as minor metabolites. 3'-Hydroxymyosmine is exclusively formed from myosmine and therefore might be used as urinary biomarker for myosmine exposure in the future.

Key words: analytical pharmacology/toxicology, excretion, GC/MS, HPLC, metabolite identification