Metabolism of Myosmine in Wistar Rats

Abstract

ABSTRACT:The alkaloid myosmine is present not only 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. 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-5-3 H]myosmine at 0.001, 0.005, 0.5, and 50 mol/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 mol/kg, a higher percentage of the radioactivity was excreted in urine (86.2 ؎ 4.9% and 88.9 ؎ 1.7%) as compared with the higher doses, 0.5 and 50 mol/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 (20-26%) and 4-oxo-4-(3-pyridyl)butyric acid (keto acid, 50-63%) using UV-diode array detection and gas chromatography-mass spectrometry 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 a urinary biomarker for myosmine exposure in the future.

Effects of Myosmine on Antioxidative Defence in Rat Liver

“…In vivo metabolism of myosmine has been investigated after oral administration in female Wistar rats by Zwickenpfl ug et al (5). The authors identifi ed 3-pyridylacetic acid (3-PAA) and 4-oxo-4-(3-pyridyl) butyric acid (keto acid) as the main metabolites and 3-pyridylmethanol, 3-hydroxymyosmine and 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) as minor …”

“…It is therefore not surprising that myosmine has also been detected in human toenail, plasma (up to 5.5 ng mL -1 ), saliva (up to 4.6 ng mL -1 ) (3) or breast milk (4). When given orally to Wistar rats, myosmine is metabolised rapidly and completely (5). After nitrosation and/or peroxidation, myosmine bioactivates to 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) and can form pyridyloxobutylated DNA adducts (6) or N'-nitrosonornicotine (NNN), which is an oesophageal carcinogen (7).…”

Investigation of the Reaction of Myosmine with Sodium Nitrite in Vitro and in Rats

“…This has led to the hypothesis that there may be sources of HPB releasing adducts other than NNN or NNK. One potential source, which has been discussed in a series of studies, is myosmine (5) (20)(21)(22)(23)(24)(25)(26).…”

Alkaloids in the human food chain – Natural occurrence and possible adverse effects

“…Due to its imine structure, myosmine may be readily converted to carcinogenic substances such as the nitrosamine N ′‐nitrosonornicotine 149, 150. Endogenous nitrosation of myosmine may lead to metabolites that have been shown in other studies to induce tumours in the upper intestinal tract (such as oesophageal adenocarcinoma), the oral cavity and the respiratory tract in rodents and humans 150–153.…”