The effect of single versus split doses of diethylnitrosamine on the induction of gamma-glutamyltranspeptidase-foci in the livers of adult and juvenile rats

The induction of gamma-glutamyltranspeptidase (GGT)-foci bysingle and by split doses of diethylnitrosamine (DENA) was evaluatedin the livers of juvenile and young adult male, Sprague-Dawleyrats. A single dose of DENA was administered at either 32, 41,46, 52 or 56 days of age and followed by a promoting regimenof sodium phenobarbital in the drinking water. In 32 day oldrats, DENA resulted in a higher incidence of GGT-foci/cm³ thanwas observed when it was administered to 41 or 46 day old rats.The same dose of DENA was inactive in 52 or 60 day old rats.In rats initiated with DENA on day 32 of age, starting the phenobarbitalpromotion at 41 days of age resulted in a higher incidence ofGGT-foci than when the phenobarbital treatment was begun at60 days of age. When the dose of DENA was split into five dailydoses of DENA starting on day 32 of age, the incidence of GGT-foci/cm³was equivalent to the single dose given on day 32 of age. However,when the five daily doses were started on 48 days of age, theincidence of GGT-foci/cm3 was less than the five doses of DENAstarted on day 32 of age. Hence, juvenile rats were more sensitiveto both single and split doses of DENA than adult rats. Thedose-response relationship was also determined in juvenile ratsfor a single and for up to 64 daily doses of 3 mg/kg DENA startedon day 32 of age. The dose-response relationship for a singledose of 3 % mg/kg DENA was equivalent to the relationship ofone to 32 daily 3 mg/kg doses. Thus, low daily doses of DENAwere additive when started in juvenile rats. Neither a thresholdnor a plateau was obtained for the dose-response relationshipof DENA initiation of GGT-foci.