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

Abstract

The induction of gamma-glutamyltranspeptidase (GGT)-foci by single and by split doses of diethylnitrosamine (DENA) was evaluated in the livers of juvenile and young adult male, Sprague-Dawley rats. A single dose of DENA was administered at either 32, 41, 46, 52 or 56 days of age and followed by a promoting regimen of sodium phenobarbital in the drinking water. In 32 days old rats, DENA resulted in a higher incidence of GGT-foci/cm3 than was 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 phenobarbital promotion at 41 days of age resulted in a higher incidence of GGT-foci than when the phenobarbital treatment was begun at 60 days of age. When the dose of DENA was split into five daily doses of DENA starting on day 32 of age, the incidence of GGT-foci/cm3 was equivalent to the single dose given on day 32 of age. However, when the five daily doses were started on 48 days of age, the incidence of GGT-foci/cm3 was less than the five doses of DENA started on day 32 of age. Hence, juvenile rats were more sensitive to both single and split doses of DENA than adult rats. The dose-response relationship was also determined in juvenile rats for a single and for up to 64 daily doses of 3 mg/kg DENA started on day 32 of age. The dose-response relationship for a single dose of 3-96 mg/kg DENA was equivalent to the relationship of one to 32 daily 3 mg/kg doses. Thus, low daily doses of DENA were additive when started in juvenile rats. Neither a threshold nor a plateau was obtained for the dose-response relationship of DENA initiation of GGT-foci.