Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Doses of chemicals which induce hepatocellular necrosis usually induce hepatic tumours if the dosing is frequent and is maintained for long periods. Such necrosis is usually evident within 48 h of the first administration. Similarly, chemicals that lead to marked proliferation of peroxisomes in the liver also usually induce hepatic tumours on pretracked regular dosing. For both of these phenomena failure to produce a certain level of effect, or to maintain it for sufficiently long periods, can result in the observation of a non-carcinogenic response. The exact dose/time requirements for carcinogenicity have not been defined and may be species/strain/sex-specific. Some chemicals induce liver enlargement and mitogenesis in the absence of overt hepatotoxic effects. The early phases of hepatomegaly are associated with mitogenic effects that can be measured as cells in S-phase within the first few days of administration. The later stages of hepatomegaly appear to be associated more with cellular hypertrophy. Both effects appear to be threshold-related. Further, sustained hepatomegaly is associated with proliferation of SER and the induction of a range of liver enzymes. These changes (mitogenesis, hepatomegaly, enzyme induction), in isolation, are less definitive indicators of carcinogenicity, but they occur for a sufficient number of liver-specific carcinogens that their role as early indicators is worthy of confirmed study. The major area of study required for all possible early markers of hepatocarcinogenicity is to establish the dose and time dependence of these changes in relation to the eventual appearance of tumours. Finally, the specificity of all these markers require evaluation by the study of appropriate non-carcinogens.
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PMID:Evidence for and possible mechanisms of non-genotoxic carcinogenesis in rodent liver. 204 85

Male rats treated with a single dose of 1,2-dibromo-3-chloropropane (DBCP) were tested for their ability to carry out the synthesis of liver proteins. In animals treated for 12 h, we found no changes in the uptake of [14C]orotic acid into liver RNA or the uptake of [3H]leucine into liver or serum protein. Uptake of [3H]leucine into the soluble fraction of the enlarged liver increased in proportion to liver size, while the uptake of [14C]orotic acid was unchanged. Examination of the ultrastructure of liver cells from rats treated for 12, 24, or 48 h revealed that the structure of the rough and smooth endoplasmic reticulum (RER; SER) were modified. An absence of ordered stacks of the RER and the presence of tangled nets of SER were noted.
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PMID:The integrity of liver protein synthesis in male rats treated with 1,2-dibromo-3-chloropropane. 618 May 25

To elucidate the effect of peroxisome proliferators on the signal-transduction pathway, we have compared the effect of ciprofibrate, an hypolipaemic agent, on the overall phosphoprotein level between rat and human well differentiated hepatic derived cell lines. The phosphorylation status of several phosphoproteins in the rat Fao cell line was increased by the drug while no changes were observed in the human HepG2 cell line. In rat Fao cells, this increase, which is concentration and time dependent, can be as much as eightfold for 20-kDa and 22-kDa proteins. Wy-14,643, a non-fibrate molecule and a more potent peroxisome proliferator than ciprofibrate, increased the phosphorylation status of the same phosphoproteins. Peroxisome proliferators may act by activating kinases inactive in control cells, by amplifying kinases already active in control cells or by inactivating phosphatases. The phosphoamino acid residues affected are essentially serine and threonine. This modification of the signal-transduction pathway by the peroxisome proliferators in rodent cells appears to be an early event or an independent mechanism of the peroxisome proliferation. These results support the accumulating evidence that the perturbation of this pathway may be a major cause of the hepatomegaly and the hepatocarcinogenesis induced by peroxisome proliferators in rodent species. In contrast, the lack of phosphorylation changes in the human HepG2 cell line supports the non-toxic effect of peroxisome proliferators also used as hypolipaemic agents in humans.
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PMID:Influence of peroxisome proliferators on phosphoprotein levels in human and rat hepatic-derived cell lines. 760 Nov 16