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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Dever
Joseph T
JT
University of Wisconsin-Madison, Department of Nutritional Sciences, Madison, WI 53706, USA.
Elfarra
Adnan A
AA
D000818:Animals; D015415:Biomarkers / Q000097:blood; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology* / Q000473:pathology; D008297:Male; D008715:Methionine / Q000097:blood* / Q000378:metabolism; D008745:Methylation; D051379:Mice; D012737:Sex Factors; D013454:Sulfoxides / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism
D015415:Biomarkers; D013454:Sulfoxides; D008715:Methionine; D000637:Transaminases