Reaction of the Tobacco Alkaloid Myosmine with Hydrogen Peroxide

Abstract

Myosmine is not only one of the minor tobacco alkaloids but is also present in various foods. Therefore, research on myosmine metabolism and activation has been intensified. 3-Pyridylacetic acid, 4-oxo-4-(3-pyridyl)butanoic acid (keto acid), 3-pyridylmethanol, 3'-hydroxymyosmine, and 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) have been identified as urinary metabolites after oral administration to female Wistar rats. Although N-nitrosation of myosmine, yielding N'-nitrosonornicotine (NNN) and HPB, was considered as a possible in vivo activation route, the formation pathways of most metabolites could not be explained until now. Therefore, under consideration of its high reactivity due to its imine structure, peroxidation of myosmine seemed to be a promising additional activation pathway. In vitro peroxidation using myosmine (8.9 micromol in 200 microL methanol) with a mixture of hydrogen peroxide (57.6 micromol, 5 microL of a 35% solution) and acetic acid anhydride (106 micromol, 10 microL) already showed high yields of reaction products after 30 min ultrasonic treatment. The product pattern was analyzed by HPLC/UV and GC/MS. Besides unchanged myosmine, 3-pyridylacetic acid, keto acid, 3-pyridylmethanol, HPB, and nornicotyrine have been identified as myosmine peroxidation products. Different product patterns were obtained after 24 h and 4 days due to a time-dependent degradation, formation, and conversion of the reaction products. Therefore, peroxidation reaction of myosmine might explain the in vivo formation of 3-pyridylacetic acid, keto acid, 3-pyridylmethanol, and HPB in rats. In addition, because of acetylating conditions using acetic acid anhydride, N-(4-oxo-4-pyridin-3-yl-butyl)acetamide was rapidly formed during the first 30 min of the reaction.

Effects of Myosmine on Antioxidative Defence in Rat Liver

“…and oral administration (see Figure 2). Furthermore, Zwickenpflug and Tyroller (6) suggested that myosmine peroxidation to 3-pyridylmethanol, nornicotyrine, HPB, and keto acid produced highly reactive electrophilic intermediates known as epoxides, and we believe that these electrophiles interact with the large nucleophilic pool of GSH in the liver and deplete it.…”

“…The increased hepatic CAT activity may be a compensatory mechanism to get rid of excess peroxides due to low GPx activity. The third is that the activation of myosmine by peroxidative or n i t r o s a t i v e m e c h a n i s m s c o u l d l e a d t o pyridyloxobutylation of proteins, DNA, and RNA (6,8,30) and could compromise their functioning.…”

“…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). In vitro experiments with calf thymus DNA have shown that myosmine is rapidly nitrosated at pH 2 to pH 4 and forms DNA adducts (8).…”

“…Zwickenpfl ug and Tyroller (6) have suggested that because of its imine structure, myosmine seems to be more reactive than other investigated tobacco alkaloids. The authors have shown that when myosmine is mixed with hydrogen peroxide, the latter attacks the carbon nitrogen double bond of the imine structure, yielding oxaziranes, nitrones, or N-oxides.…”

Flow Cytometric Analysis of the Influence of Myosmine on the Cell Cycle

“…4 After nitrosation and/or peroxidation, myosmine gives rise to reactive pyridyloxobutylating species which are capable of forming pyridyloxobutylated DNA adducts. [5][6][7][8] Nitrosation of myosmine also leads to the formation of the esophageal carcinogen N '-nitrosonornicotine. 5 Originally, nitrosonornicotine and 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing adducts were thought to be highly tobacco-specific.…”