The methionine analog S-methylthiocysteine stimulates neutral amino acid transport by isolated brain microvessels

Abstract

Abstract As an extension of the hypothesis suggesting that the role of hyperammonemia and of plasma amino acid imbalance in the pathogenesis of hepatic encephalopathy is mediated by glutamine formation at the level of the blood-brain barrier, the possible effects of mercaptans on neutral amino acid transport by isolated brain microvessels were investigated. In this experimental system, methanethiol as such had no effect on any of the neutral amino acid transport systems. If the isolated brain microvessels were preloaded in the presence of both methanethiol and cystine (or cysteine), there was a marked stimulation of the L-system-mediated uptake of hydrophobic (branched or aromatic) neutral amino acids, this enhancement being similar to that caused by glutamine preloading. Cystine or cysteine alone were ineffective, nor could they be replaced by other non-sulfur-containing amino acids. The stimulation of the L-system could be attributed to the formation of S -methylthiocysteine, a mixed disulfide whose chemical structure is similar to that of methionine. S -methylthiocysteine was found to be formed spontaneously, upon preincubation with methanethiol plus cystine or cysteine, within the endothelial cells of isolated brain microvessels. Methanethiol, via S -methylthiocysteine formation, appears therefore to deserve a place, synergistically with the ammonia-glutamine system, among the precipitating causes of hepatic encephalopathy.