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

Abstract

Previous studies have shown that the minor tobacco alkaloid myosmine (5) reacts with NaNO 2 in the presence of acid to yield 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB, 8) via 4-(3-pyridyl)-4-oxobutanediazohydroxide (7). Intermediate 7 is also formed in the metabolism of the tobacco-specific nitrosamines N′-nitrosonornicotine (NNN, 1) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 2), resulting in pyridyloxobutylation of DNA and Hb. These pyridyloxobutyl adducts can be quantified by analyzing HPB released upon acid treatment of DNA or base treatment of Hb. Quantitation of HPB-releasing DNA and Hb adducts has been used to assess the metabolic activation of NNN and NNK in smokers and smokeless tobacco users. Since myosmine is found in the diet as well as in tobacco products, it has been suggested that nitrosation of myosmine could lead to the formation of HPB-releasing adducts in people not exposed to tobacco products. We investigated the nitrosation of myosmine in vitro and in vivo in rats. Reaction of myosmine with NaNO 2 under acidic conditions produced HPB, as previously reported. A new product was identified as 3′-oximinomyosmine (11) based on its spectral properties. NNN was not detected. Groups of rats were treated with NNN, NNK, myosmine, NaNO 2 , or combinations of myosmine and NaNO 2 . HPBreleasing Hb and DNA adducts were clearly detected in the rats treated with NNN or NNK, but we found no evidence for production of these adducts from the combination of myosmine plus NaNO 2 . The results of this study do not support the hypothesis that exposure to dietary myosmine could lead to HPB-releasing DNA or Hb adducts in humans.

4-Hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in lung, lower esophagus and cardia of sudden death victims

“…The data are also consistent with results on HPB-releasing hemoglobin adducts used as a surrogate marker for DNA adducts (Carmella et al, 1990;Falter et al, 1994;Branner et al, 1998;Atawodi et al, 1998;Hölzle et al, 2007). Until now, only NNN, NNK and NNAL have been identified as possible sources of HPB-releasing adducts in DNA from lung and esophagus of experimental animals (Hecht, 1999;Hecht et al, 2007;Lao et al, 2007a,b). However, the high levels of HPB-releasing adducts in lung, esophagus and cardia, which are totally independent from the smoking status (Table 2) and correspond to a mean of 22, 41 and 33 adducts in 10 8 normal nucleotides, respectively, must have other sources in addition to TSNA.…”

“…One possible source could be the minor tobacco alkaloid myosmine which also occurs in a wide variety of staple foods, vegetables, fruits and dairy products Tyroller et al, 2002). On nitrosation and peroxidation myosmine gives rise to a reactive pyridyloxobutylating species capable of forming HPB-releasing adducts (Wilp et al, 2002;Zwickenpflug, 2000;Zwickenpflug and Tyroller, 2006;Hecht et al, 2007). Higher HPB-releasing DNA adduct levels in the mucosa of esophagus and cardia as compared to peripheral lung tissue may be explained by optimal nitrosation conditions for myosmine from saliva and food at the entrance to the stomach (Tyroller et al, 2002;Suzuki et al, 2003Suzuki et al, , 2005Maier et al, 2005;Combet et al, 2007).…”

Isolation of Nicotinic Acid (Vitamin B3) and N-Propylamine after Myosmine Peroxidation

“…5 Moreover, 7 generation was observed under myosmine N-nitrosation conditions. 6,7 In this context it should be noted the formation of 7 was originally observed in studies on the carcinogenic effects of tobacco-specific N-nitrosamines (TSNA), N-nitrosonornicotine (NNN), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). 8 The activation of NNN and NNK through hydroxylation by P450 isoenzymes yielded a highly reactive 4-(3-pyridyl)-4-oxobutane-diazohydroxide converted to the 4-(3-pyridyl)-4-oxobut-1-yl (POB) intermediate which was shown to interact with DNA and protein.…”

“…9 Following studies conducted under treatment of rats with dietary 1 and NaNO 2 in drinking water yielded no significant HPB-releasing DNA in lung, liver, or esophagus compared to rats administered with NaNO 2 alone. 6 The relevance of 7 formation by 1 resulting from pyridyloxobutylated-DNA adducts is not cleared. Extensive studies which demonstrate the toxicological potency of the TSNA, NNN, and NNK were not conducted in a manner similar to that of 1 until now.…”

MYMD-1, a Novel Immunometabolic Regulator, Ameliorates Autoimmune Thyroiditis via Suppression of Th1 Responses and TNF-α Release

“…Nicotine and anatabine, however, similarly nornicotine and anabasine, undergo nitrosylation during the curing process, leading to the formation of tobacco-specific N9-nitrosamines that are carcinogenic (21). On the contrary, myosmine and isonicoteine do not form tobacco-specific N9-nitrosamines in vivo (22) and are thus more amenable to clinical applications. We designed the current study to assess the effect of MYMD-1, a synthetic tobacco alkaloid derivative, in the NOD.H-2 h4 mouse model of autoimmune thyroiditis.…”