DL-methionine methylsulfonium chloride: Effects on Gastric Conditions and Adipocyte Differentiation

DL-methionine methylsulfonium chloride is a naturally occurring methionine derivative. DL-methionine methylsulfonium chloride protects gastric mucosal from ethanol-induced damage.

DL-methionine methylsulfonium chloride in the Healing of Erosive Gastritis

One milliliter of 1, 2, or 5% DL-cysteine (cysteine) or DL-methionine methylsulfonium chloride (MMSC) was instilled into the rat stomach 1, 24, and 48 h after giving ethanol (1 mL of 40% solution) by gavage. One hour following the administration of ethanol, gastric mucosal injury was seen in all the animals (22.6 ± 1.1 mm2, mean ± SEM; n = 10). Twenty-four hours after giving the ethanol, all the rats treated with cysteine or DL-methionine methylsulfonium chloride still had the mucosal injury. Treatment with 2% cysteine or MMSC significantly (p < 0.01) reduced the extent of this injury (10.2 ± 0.6 and 10.1 ± 0.5 mm2, respectively, versus 20.7 ± 1.2 mm2, mean ± SEM; n = 10), an action that was similarly achieved by the 5% solutions (10.1 ±0.5 and 9.9 ± 0.3 mm2, respectively, versus 20.7 ± 1.2 mm2, mean ± SEM; n = 10). Forty-eight hours following the administration of ethanol, 30% of the animals given 1% cysteine or MMSC still had gastric mucosal injury, which was significantly (p < 0.001) less extensive than that seen with ethanol alone (3.8 ± 0.3 and 4.1 ± 0.3 mm2, respectively, versus 13.1 ± 0.8 mm2, mean ± SEM; n = 10). [1]

At this time period, however, none of the animals treated with 2 or 5% solutions of cysteine or DL-methionine methylsulfonium chloride still had any injury. Healing of the ethanol-induced injury was confirmed microscopically and was achieved by regeneration. Chronic gastric ulceration was produced in the rat by administering 5 mg/kg of reserpine ip every day for 5 days, then housing the animals for 2 weeks. Cysteine and DL-methionine methylsulfonium chloride (1 mL by gavage daily) demonstrated a dose-dependent and time-related power to stimulate the healing of this ulceration. After gavaging for 5 days, 80% of the rats given 1% cysteine and 70% of those given 1% MMSC had gastric ulceration, whereas only 20% of the animals given 10% solutions had the ulceration. After gavaging for 10 days, 20% of the rats given 1% cysteine and 30% of those given 1% DL-methionine methylsulfonium chloride had gastric ulceration, whereas none gavaged with 5 or 10% solutions of these agents still had any ulceration. At this stage, 70% of the animals gavaged with distilled water still had the ulceration. These cysteine and DL-methionine methylsulfonium chloride actions were independent of any effect on the gastric acid secretion. The results show that sulfhydryl-containing agents stimulate the healing of ethanol-induced acute gastric mucosal injury and chronic gastric ulceration in the rat.

Inhibitory Effect of DL-methionine methylsulfonium chloride

DL-methionine methylsulfonium chloride was originally called vitamin U because of its inhibition of ulceration in the digestive system. Vitamin U is ubiquitously expressed in the tissues of flowering plants, and while there have been reports on its hypolipidemic effect, its precise function remains unknown. Recently, a number of natural compounds, such as herbal drugs and flavonoids, have received considerable attention for their abilities to regulate adipogenesis. S-methylmethionine sulphonium chloride is abundant in the tissues of flowering plants, especially in raw cabbage, and has also been called vitamin U (from the Latin 'ulcus' meaning sore or ulcer), although its classification as a vitamin has not yet been accepted. Gessler et al. reported that vitamin U can decrease the level of lipid peroxidation and inhibit monoamine oxidase activity. Also, they reported that DL-methionine methylsulfonium chloride has a hypolipidemic effect.[2]

This study suggests that vitamin U inhibits adipocyte differentiation via down-regulation of adipogenic factors. We investigated the effects of DL-methionine methylsulfonium chloride on the inhibition of intracellular TG and G3PDH activities, marker enzymes of adipogenesis, in 3T3-L1 adipocytes. Fasting induces conversion of glycerol into TG through an induction of several hepatic enzymes such as G3PDH and glycerol kinase. Tomiyama et al. indicated that the expression of G3PDH is induced several fold upon conversion of preadipocytes to adipocytes, which is the predominant substrate for TG synthesis in adipose tissue. Our data indicated that the exposure of 3T3-L1 adipocytes to DL-methionine methylsulfonium chloride results in lower levels of intracellular TGs and G3PDH than did other compounds tested. Adipose tissue is now known to produce and secrete PPAR-γ, C/EBP-α, ADD-1 and adipsin, which have roles in adipocyte differentiation because they are transcriptional factors for numerous genes. The present experiment indicated that DL-methionine methylsulfonium chloride treatment inhibited the mRNA expression levels of PPAR-γ, C/EBP-α, ADD-1 and adipsin, which demonstrates that adipogenesis is inhibited by the upstream transcriptional factor cascade. There were no noticeable changes in mRNA levels of LPL or FAS, which indicates that vitamin U does not affect adipocyte function itself. The effects of vitamin U on adipocyte differentiation were evaluated using Oil Red O staining and through the analysis of cellular TG content and G3PDH activity.

Here, we present evidence that DL-methionine methylsulfonium chloride inhibits adipocyte differentiation through the activation of AMPK. AMPK is a well-known metabolic master switch, activated by various stimuli, including exercise, hypoxia and reactive oxygen species. Once activated, AMPK blocks anabolic pathways and promotes catabolic pathways, protecting the cell from various stress stimuli. Hwang et al. suggested that several naturally occurring compounds, such as genistein, EGCG and capsaicin, activate AMPK in a dose-dependent manner, leading to the inhibition of adipocyte differentiation. Although we found that AMPK and adipocyte differentiation factors (PPAR-γ, C/EBP-α, ADD-1 and adipsin) are involved in the antiobesity effects exerted by DL-methionine methylsulfonium chloride, no direct correlation was found between AMPK and the signaling pathways of other adipocyte differentiation factors. Therefore, possible connections between AMPK and the signaling pathways of other adipocyte differentiation factors should be investigated in future studies. In the present study, we elucidated the inhibitory effects of vitamin U on 3T3-L1 adipocytes, as indicated by decreases in intracellular TG content and G3PDH activity. The inhibitory effect of DL-methionine methylsulfonium chloride appears to be mediated by the down-regulated expressions of adipogenic transcription factors (PPAR-γ, C/EBP-α and ADD-1) and adipocyte-specific proteins (adipsin) and the upregulated expression of AMPK. Since obesity is a social issue and a well-established risk factor for cardiovascular disease and diabetes, our study suggests that it may be worthwhile to determine if DL-methionine methylsulfonium chloride has an inhibitory effect on adipogenesis in vivo.

Effect of DL-methionine methylsulfonium chloride on oesophagogastric ulcers

There was no difference over the 49 d in weight gain, feed intake and backfat in pigs with and without DL-methionine methylsulfonium chloride supplementation between pigs with or without fully developed oesophagogastric ulcers at the start of the study. In pigs with an initially low ulcer score, feeding SMMSC did not prevent further oesophagogastric ulcer development. No significant effect of DL-methionine methylsulfonium chloride was apparent when final mean oesophagogastric ulcer scores were compared in pigs with existing high ulcer score. However, further analysis of the changes in individual pig oesophagogastric ulcer scores during the experiment showed that the observed reductions in scores of the high ulcer group was significantly different from all other groups.[3]

This study has indicated that supplementation of pig diets with DL-methionine methylsulfonium chloride cannot be justified unless the slight ulcer score improvement observed could be translated to some commercial production advantage such as a reduction in pig mortalities due to oesophagogastric ulcers. This study has further confirmed the benefit of endoscopy as a tool to enable objective assessment of oesophageal gastric health.

References

[1]Salim AS. Role of sulfhydryl-containing agents in the healing of erosive gastritis and chronic gastric ulceration in the rat. J Pharm Sci. 1992 Jan;81(1):70-3.

[2]Lee NY, Park KY, Min HJ, Song KY, Lim YY, Park J, Kim BJ, Kim MN. Inhibitory Effect of Vitamin U (S-Methylmethionine Sulfonium Chloride) on Differentiation in 3T3-L1 Pre-adipocyte Cell Lines. Ann Dermatol. 2012 Feb;24(1):39-44.

[3]Kopinski JS, Fogarty R, McVeigh J. Effect of s-methylmethionine sulphonium chloride on oesophagogastric ulcers in pigs. Aust Vet J. 2007 Sep;85(9):362-7.

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