Reversibility and persistence of di-2-ethylhexyl phthalate (DEHP)- and phenobarbital-induced hepatocellular changes in rodents

The tumor promotion stage of chemical carcinogenesis has been shown to exhi bit a persistence of cellular effects during treatment and the reversibilit y of these changes upon cessation of treatment. Inhibition of gap-junctiona l intercellular communication and increased replicative DNA synthesis appea r to be important in this process. The present study assessed the persisten ce and reversibility of gap-junctional intercellular communication inhibiti on, peroxisomal proliferation, and replicative DNA synthesis in livers from male F344 rats and B6C3F1 mice. Dietary administration of 20,000 mg/kg DEH P to male rats for 2 weeks decreased intercellular communication (67% of co ntrol) and enhanced replicative DNA synthesis (4.8-fold over control). Elev ation of the relative fiver weight and the induction of peroxisomal beta ox idation were also observed following treatment with 20,000 mg/Kg DEHP for 2 weeks. Following DEHP administration at a dose of 6000 mg/kg for 18 months , inhibition of gap-junctional intercellular communication persisted, and t he relative liver weight and induction of peroxisomal beta oxidation remain ed elevated in both rats and male B6C3F1 mice. Treatment of rats and mice w ith phenobarbital for 18 months (500-mg/kg diet) also produced an increase in relative liver weight and a decrease in cell-to-cell communication. In r ecovery studies in which DEHP was administered to male F344 rats for 2 week s and then withdrawn, the relative liver weight, rate of peroxisomal beta o xidation, increase in replicative DNA synthesis, and inhibition of gap-junc tional intercellular communication returned to control values within 2 to 4 weeks after DEHP treatment ceased. Recovery studies with phenobarbital pro duced similar results. The primary active metabolite of DEHP, mono-2-ethylh exyl phthalate (MEHP), was detected in the livers of animals treated with D EHP for greater than 2 weeks. However, it could not be detected after remov al of DEHP from the diet for 2 weeks. This study demonstrated that inhibiti on of gap-junctional intercellular communication, along with indicators of peroxisomal proliferation, including increased relative liver weight and en hanced peroxisomal beta oxidation, persist while DEHP treatment continues b ut reverses when treatment is stopped. Studies with phenobarbital produced a similar pattern of response.