On the role of compensatory mitogenesis in the hepatocarcinogenicity of choline and multiple-lipotrope devoid diets

Female F-344 rats, in contrast to male rats of the same strain, are largely resistant to the hepatonecrogenic and hepatocarcinogenic actions of a diet devoid of choline and restricted in methionine (CD diet). A study was performed to determine whether the resistance would be overcome by feeding a diet devoid not only of choline, but also of methionine, vitamin B12 and folic acid (MGD diet). Three experiments were performed, to compare the degrees of steatosis and cell death and proliferation, and the onset of pre-neoplastic and neoplastic lesions, in the liver of female F-344 rats fed either the CD or the MGD diet. Limited responses were again observed in rats fed the CD diet. On the other hand, feeding the MGD diet resulted in degrees of steatosis and of compensatory mitogenesis comparable to those previously found to occur in male F-344 rats fed the CD diet. It resulted also in the development of a marked cirrhosis, of neoplastic nodules and of hepatocellular carcinomas. The results indicate that in female F-344 rats overall availability of methyl groups may be more critical than the dietary supply of choline in determining the severity and spectrum of hepatopathology. They emphasize also the importance of compensatory mitogenesis in the induction of neoplastic lesions by methyl-group deficient or devoid diets.