Adaptive Liver Growth Induced by Xenobiotic Compounds: Its Nature and Mechanism

Abstract

Several drugs and environmental pollutants which are known to stimulate hepatic drug-metabolizing enzyme activity, liver growth, and multiplication of the endoplasmic reticulum, have recently been found to produce liver tumors in rodents. These “xenobiotic” agents include phenobarbitone, steroid hormones such as cyproterone acetate (CPA) or norethisterone, and organochlorine compounds such as DDT, hexachlorocyclohexane (HCH, lindane), hexachloroben-zene etc. Available evidence suggests that the prolonged induction of growth is responsible for the tumorigenic activity of these agents. Therefore it seems useful to consider some findings relevant to an understanding of the nature and mechanism of the induced growth.

During short-term treatment the inducers produce liver enlargement which, in the rat, is usually due to a combination of hypertrophy and hyperplasia as shown by increases of total DNA content, parenchymal DNA synthesis and mitotic activity. Histological and biochemical analyses revealed no signs of significant liver cell damage. The response is self-limited, dose-dependent and reversible (with the partial exception of the hyperplastic component of the growth process). Obviously, in short-term experiments liver size and cell content are shifted to a new steady state at an increased level, without disturbance of homeostasis of growth control, as would be expected of an adaptive process.

Elucidation of the mechanism by which the inducers stimulate growth requires identification of the nature and sequence of regulative events which control the initiation of DNA and cell replication in the liver in vivo. Two such events were found by means of certain feeding schedules and of actinomycin D, an inhibitor of RNA synthesis: To trigger off the replicative cycle at the “starting point” food consumption is required, and a step is necessary which is sensitive to low doses of actinomycin D. Several hours later cells committed to replication reach the “R-point” at which amino acids are needed to permit further progress towards commencement of DNA synthesis (“Two-Stage Control”). Hopefully, such information may be useful to discriminate between different types of growth. It appears that some regulative features of cell proliferation induced by α-HCH and similar inducers resemble those found during physiologic or adaptive growth of adolescent rat liver, and differ from those observed after administration of hepatotoxic or hepatocarcinogenic compounds.

In conclusion we have not found evidence indicating that a disturbance of growth control might be an early effect of the xenobiotic inducers, and we suggest that liver tumor formation may be due to promotion of tumor development from pre-existent tumorigenic lesions, resulting from the prolonged and excessive stimulation of growth.