Expression of the immediate-early genes, c-fos, c-jun, and c-myc: a comparison in rats of nongenotoxic hepatocarcinogens with noncarcinogenic liver mitogens.
The involvement of the immediate-early (IE) genes c-fos, c-jun, and c-myc in regenerative liver hyperplasia is accepted, but their involvement in direct hyperplasia is uncertain. We have examined the hypothesis that the ability to induce IE genes may reflect the hepatocarcinogenic potential of a chemical. The ability of 1,4-dichlorobenzene (DCB) (300 mg/kg) (a noncarcinogenic rat liver mitogen), diethylhexyl phthalate (DEHP) (950 mg/kg), and chlorendic acid (120 mg/kg) (both nongenotoxic hepatocarcinogens) to induce c-fos, c-jun, and c-myc expression in rat liver was determined by Northern blot analysis and by in situ hybridization. Results were correlated to hepatic labeling index (LI) as determined by incorporation of BrdU in each of three lobes for each of three male F344 rats per group. Carbon tetrachloride (CCl4) (2 ml/kg) was used as a positive control. Increased LI was preceded by elevated expression of all three IE genes after CCl4, but also after DCB and DEHP, although induction by these was less marked. In all cases, there was considerable interanimal variation within groups, but little interlobe variation. Interestingly, there was a good correlation (r2 > or = 0.85) between c-myc expression and LI, but not between LI and c-fos or c-jun. Despite the disparate carcinogenic potential of DEHP and DCB, both chemicals induced similar patterns of IE gene expression, suggesting that this cannot distinguish hepatocarcinogenic liver mitogens from noncarcinogenic liver mitogens. These data assist in the evaluation of IE gene expression both as a marker of direct versus regenerative hyperplasia and as an indicator of the hepatocarcinogenic potential of liver mitogens.
Hasmall
S C
SC
Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, United Kingdom.
Pyrah
I T
IT
Soames
A R
AR
Roberts
R A
RA
D000818:Animals; D015152:Blotting, Northern; D002273:Carcinogens / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D004247:DNA / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000187:drug effects*; D017403:In Situ Hybridization; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008934:Mitogens / Q000633:toxicity*; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D008934:Mitogens; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D004247:DNA