Alteration of S-adenosylmethionine synthetases during chemical hepatocarcinogenesis and in resulting carcinomas.

S-Adenosylmethionmne synthetase isozymes (EC 2.5.1.6) were studied in hepaticnodules,primaryhepatocellularcarci nomas, and various transplantable hepatocellulan carcinomas induced by acetylaminofluomene. With the exception of hepa toma 7800, the intermediate-Km isozyme was the only enzyme species detectable in transplantable hepatomas, including 7777, 31 i C, 253, 252, 56, and Novikoff hepatoma. Although hepatoma 7800 retained all of the hepatic isozymes, the levels of various isozymeswere different from thoseof normalliver. During acetylaminofluorene hepatocarcinogenesis, there was an alteration in enzyme composition that commenced in neo plastic nodules and eventually attained the pattern commonly observed for many primary and transplantable hepatocellulam carcinomas. Evidence is presented which indicated that the intermediate-Km isozyme of Novikoff hepatoma was derived from the IOWKmisozyme and that protein factors were partly responsible for this higher Km. This alteration of the kinetic properties of tumor isozyme was unique to neoplastic nodules and tumors and therefore may be a significant characteristic of malignant evolution. The existence of s-adenosylmethionine synthetase-tRNA methyltransferase complex was supported by the demonstration of cochromatography of these two enzymes on Sephamose6B, coprecipitation at pH 5, and a higher effi ciency of utilization of S-adenosylmethionine synthesized by S adenosylmethionmnesynthetase by tRNA methyltransfemasesin the enzyme complex than that provided exogenously. After pH 5 treatment, the majority of tumor enzyme complex retained the complex form, whereas liver enzyme complex was almost totally dissociated, indicating that tumor enzyme complex was more stable than liver enzyme complex against pH variations. The difference in the stability of this enzyme complex is prob ably attributable to the factors characteristically associated only with S-adenosylmethionine synthetase from neoplastic tissues.