Correlation of isozyme patterns of S-adenosylmethionine synthetase with fetal stages and pathological states of the liver.

The liver is the most active organ engaged in S-adenosyl methionine metabolism . S-Adenosylmethionine synthetase isozymes (EC 2.5.1 .6) were studied in normal, fetal, and pathological livers including hepatoma to correlate their activities with developmental stages and pathophysiologi cal states of the liver. Three isozymes of S-adenosylme thionine synthetase, namely low, intermediate, and high Km, have been identified from adult rat and human livers. The Km(methionine) are 3.6 @M, 23 @M, and 1.03 mM for the rat liver isozymes and 3.1 jIM, 20 pM, and 0.65 mM for the human liven isozymes. The high-Km isozyme could be distin guished from other isozymes by its dependency on sulfhy dryl reagents, activation by dimethyl sulfoxide, and chro matographic behaviors on Sepharose 6B and DEAE-cellu lose columns. The activity of the low-K,,, isozyme, and to a lessen extent that of the intermediate-Km i5O@\fme,was greatly enhanced in livers characteristic of rapid growth, such as in fetal, newborn, and regenerating livers. In contrast, the activity of the high-Km isozyme was undetect able in fetal livers and was greatly reduced during the growth phase of remnant liver following partial hepatec tomy. Only the intermediate-Km isozyme was detectable in rat Novikoff hepatoma, indicating a unique metabolic fea tune associated with this tumor with respect to isozymes of S-adenosylmethionine synthetase. Such an aberration may have significant bearing on liver neoplasia. Livers of pa tients who died of hereditary tyrosinemia showed abnormal isozyme patterns of S-adenosylmethionine synthetase. The high-Km isozyme was either undetectable, thus resembling the fetal pattern, on present in a relatively low amount. It is suggested that abnormal development of S-adenosylme thionine synthetase isozymes may be partly responsible for abnormal methionine metabolism and hepatic dysfunctions often associated with these patients.