Effect of 3-deazaadenosine on methionine metabolism in isolated perfused livers

Duerre, John A.

doi:10.1139/o88-119

Cited by 7 publications

(2 citation statements)

References 23 publications

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“…Exposure to 3-DA is known to result in increased SAM and SAH levels and inhibition of methylation reactions in liver (Duerre, 1988;Prytz and Aarbakke, 1990). The buildup of SAM results in feedback inhibition of MAT activity (Finkelstein, 1990).…”

mentioning

confidence: 99%

l-Methionine Toxicity in Freshly Isolated Mouse Hepatocytes Is Gender-Dependent and Mediated in Part by Transamination

Dever¹,

Elfarra²

2008

J Pharmacol Exp Ther

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L-Methionine (Met) has been implicated in parenteral nutritionassociated cholestasis in infants and, at high levels, it causes liver toxicity by mechanisms that are not clear. In this study, Met toxicity was characterized in freshly isolated male and female mouse hepatocytes incubated with 5 to 30 mM Met for 0 to 5 h. In male hepatocytes, 20 mM Met was cytotoxic at 4 h as indicated by trypan blue exclusion and lactate dehydrogenase leakage assays. Cytotoxicity was preceded by reduced glutathione (GSH) depletion at 3 h without glutathione disulfide formation. Exposure to 30 mM Met resulted in increased cytotoxicity and GSH depletion. It is interesting to note that female hepatocytes were resistant to Met-induced cytotoxicity at these concentrations and showed increased cellular GSH levels compared with hepatocytes exposed to medium alone. The effects of amino-oxyacetic acid (AOAA), an inhibitor of Met transamination, and 3-deazaadenosine (3-DA), an inhibitor of the Met transmethylation pathway enzyme S-adenosylhomocysteine hydrolase, on Met toxicity in male hepatocytes were then examined. Addition of 0.2 mM AOAA partially blocked Met-induced GSH depletion and cytotoxicity, whereas 0.1 mM 3-DA potentiated Met-induced toxicity. Exposure of male hepatocytes to 0.3 mM 3-methylthiopropionic acid (3-MTP), a known Met transamination metabolite, resulted in cytotoxicity and cellular GSH depletion similar to that observed with 30 mM Met, whereas incubations with D-methionine resulted in no toxicity. Female hepatocytes were less sensitive to 3-MTP toxicity than males, which may partially explain their resistance to Met toxicity. Taken together, these results suggest that Met transamination and not transmethylation plays a major role in Met toxicity in male mouse hepatocytes.

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mentioning

confidence: 99%

l-Methionine Toxicity in Freshly Isolated Mouse Hepatocytes Is Gender-Dependent and Mediated in Part by Transamination

Dever¹,

Elfarra²

2008

J Pharmacol Exp Ther

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“…3) [11–13]. Addition of the SAH hydrolase and Met TM inhibitor 3-deazaadenosine (3-DA) [63] significantly potentiated Met-induced cytotoxicity in male FIMHs compared with those exposed to only Met [11] (Fig. 3C).…”

Section: Methionine Metabolism: Physiological Roles and Toxicologimentioning

confidence: 99%

The biochemical and toxicological significance of hypermethionemia: new insights and clinical relevance

Dever

Elfarra

2010

Expert Opinion on Drug Metabolism & Toxicology

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Importance of the field-Disrupted L-methionine (Met) metabolism can lead to hepatic, neurological, and cardiovascular dysfunction in humans. Aberrant methyl group flux likely contributes to the development of these pathologies, but when patients also become hypermethionemic, additional toxicological mechanisms may be relevant.Areas covered in this review-Following a discussion of the causes of hypermethionemia in humans, evidence for the toxicological roles and clinical significance of the Met transmethylation (TM), transamination (TA) and sulfoxidation (SO) pathways will be presented.What the reader will gain-Recent data from freshly-isolated mouse hepatocytes (FIMHs) confirmed previous in vivo results in rodents that Met TM is a detoxification pathway while Met TA leads to toxicity. Gender-related differences in Met accumulation and metabolism in FIMHs correlated with gender differences in toxicity. Data obtained from FIMHs also implicated Met SO in Met metabolism and toxicity. Currently, little is known about the mechanisms and biological significance of Met sulfoxidation in humans.Take home message-In hypermethionemic patients, clinical and dietary interventions should focus on increasing Met TM and decreasing Met TA and SO. Novel biomarkers of hypermethionemia in humans that correlate with pathological end points are needed to better understand the impact of the condition.

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Effect of the methylation inhibitors 3-deazaadenosine and 3-deazaaristeromycin on phosphatidylcholine formation in Tetrahymena

Smith

Ledoux

1990

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metaboli

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Effect of 3-deazaadenosine on methionine metabolism in isolated perfused livers

Cited by 7 publications

References 23 publications

l-Methionine Toxicity in Freshly Isolated Mouse Hepatocytes Is Gender-Dependent and Mediated in Part by Transamination

l-Methionine Toxicity in Freshly Isolated Mouse Hepatocytes Is Gender-Dependent and Mediated in Part by Transamination

The biochemical and toxicological significance of hypermethionemia: new insights and clinical relevance

Effect of the methylation inhibitors 3-deazaadenosine and 3-deazaaristeromycin on phosphatidylcholine formation in Tetrahymena

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