Induction of liver cytochrome P4502E1 by pyrazole and 4-methylpyrazole in neonatal rats

Cytochrome P4502E1 (P4502E1) is not present in fetal rat liver; activation of the gene occurs within hours after birth. In adult rats, chemical inducers increase P4502E1 levels largely by a post-transcriptional type of mechanism. Experiments were carried out to evaluate how soon after birth chemicals such as pyrazole or 4-methylpyrazole (MP) can induce P4502E1 and whether the mechanism for induction at these early developmental stages, during active transcription, is different from that found in adults. No P4502E1 was found in fetal liver; in liver microsomes from saline control rats, there was a progressive increase in P4502E1 levels and oxidation of dimethylnitrosamine every 2 days after birth, with maximal levels 8 to 14 days after birth. Injecting pyrazole and MP on day 0 and day 1 after birth, resulted in 2- to 4-fold increases (compared to saline control values) in P4502E1 content and oxidation of dimethylnitrosamine in liver microsomes isolated from 2-day-old pups. This extent of increase by treatment with pyrazole or MP over saline control values was similar to that found when pups were treated for 2 days with the inducers on days 2, 4, 6, 8, 12 and 19 after birth. Northern blot analysis indicated a progressive increase in P4502E1 mRNA levels, reaching a maximum at about 8 days after birth for saline-treated pups. Pyrazole or MP did not increase P4502E1 mRNA levels over values for the saline controls. These results indicate that P4502E1 protein and catalytic activity can be induced immediately after birth by pyrazole and MP, and that the extent of induction is as effective as in later times of the neonatal period. The mechanism of induction, similar to that found with adult rats, appears to involve a post-transcriptional effect.