Tissue Cystathionine in Mice Treated With Cysteine and Homoserine

Extract: Mouse brain was demonstrated to concentrate DL-homoserine and L-cysteine from plasma. Simultaneous injection of 7.5 μmoles DL-homoserine and L-cysteine intraperitoneally to mice resulted in a marked increase of brain cystathionine at the end of 5 hr. The concentration of cystathionine in the experimental group (0.143 ± 0.022 μmole/g) was more than 6 times that of the control group (0.023 ± 0.011 μmole/g). By using unlabeled DL-homoserine and DL-cysteine-35S for injection, cystathionine in brain was found to be labeled, with a specific activity (67,800 dpm/μmole) approximately half that in the radioactive cysteine (115,000 dpm/μmole). These observations suggest that approximately half the cystathionine in brain has been derived from cysteine and, presumably, homoserine. The remaining half is presumed to have been derived from methionine. Chronic feeding of diets containing 5%, 2%, and 1% DL-homoserine and L-cysteine, 5% and 2% DL-homoserine, and 5%, 2%, and 1% L-cysteine to weanling mice resulted in a significant increase in cystathionine in brain compared with controls (0.148 ± 0.016, 0.049 ± 0.002, 0.044 ± 0.002, 0.040 ± 0.001, 0.043 ± 0.003, 0.069 ± 0.003, 0.036 ± 0.002, 0.034 ± 0.002, and 0.027 ± 0.003 μmole/g, respectively). After 34 weeks of dietary experiments, the animals fed with diets containing 5%, 2%, and 1% of both DL-homoserine and L-cysteine, 5% DL-homoserine, and 5% and 2% L-cysteine had significantly lower body weight than that of the controls (22.02 ± 0.290, 26.00 ± 0.460, 26.40 ± 0.462, 25.50 ± 0.504, 23.10 ± 0.388, 25.82 ± 0.512, and 28.53 ± 0.786 g, respectively). The lower weight gained in the experimental animals was correlated with less food intake. Autopsy on all the experimental animals and light microscopy of their brains, lungs, hearts, livers, spleens, suprarenals, kidneys, and intestines showed no pathology. However, electron microscopy of the livers of animals fed with diets containing 5% cysteine showed subcellular changes compatible with poor nutrition, possibly related to inadequate food intake. Animals on all the experimental diets remained fertile; they conceived and produced normal litters. Speculation: The observations reported in this paper demonstrated that cystathionine in brain was increased when mice were given cysteine and homoserine either by intraperitoneal loading or by chronic feeding. It is very probable that tissue cystathionine (particularly that of the brain) may be increased in patients with homocystinuria when adequate amounts of cysteine (or cystine) and homoserine are supplied in the diet. Excessive cysteine may produce unpalatability of the diet. However, this may be corrected by reducing the quantity of cysteine added, flavoring the diet, or by replacing the cysteine with cystine or calcium cystinate. Supplementation of cysteine (or cystine) and homoserine may be the only way to correct cystathionine deficiency in patients with pyridoxine-resistant homocystinuria. Our observations provide the biochemical basis for investigating the possible therapeutic value of supplementing the diet of homoeystinurie patients with cysteine (or cystine) and homoserine.