Suppression of hepatic levels of an ethanol-inducible P-450DM/j by growth hormone: relationship between the increased level of P-450DM/j and depletion of growth hormone in diabetes.

The mechanism of the suppression of an ethanol-inducible cytochrome P-450 (P-450DM/j) by pituitary hormone has been studied in rats. The hepatic content of P-450DM/j protein quantitated by Western blots was low but was 2-fold higher in male than female untreated rats (75 and 34 pmol/mg of protein, respectively). The content was increased 2.6-fold (male) and 5.6-fold (female) by hypophysectomy and the sex-related difference was abolished. Treatment of hypophysectomized rats with human growth hormone (hGH), but not with prolactin, reversed the increased amounts of P-450DM/j protein. The hGH-induced suppression was more effective with the continuous infusion than intermittent injection. The hepatic level of P-450DM/j mRNA, determined by the use of a 23-mer oligonucleotide probe, was also changed by hypophysectomy and/or hGH-treatment, largely in parallel with the changes in the content of P-450DM/j protein and microsomal p-nitrophenol and aniline hydroxylations. These results suggest that growth hormone exerts the suppressive effect on P-450DM/j through a somatogenic receptor-mediated process. In another growth hormone-depleted condition, diabetes, the hepatic level of P-450DM/j mRNA was also increased to a level similar to that in hypophysectomized rats, but the protein content was 2- to 3-fold higher in diabetic than hypophysectomized rats. These results indicate, in addition to the reduction of serum growth hormone level, the presence of another stimulatory factor, which acts translationally or posttranslationally in livers of diabetic rats. On the other hand, coordinate changes in the level of P-450DM/j protein and the mRNA in hypophysectomized rats indicate that growth hormone acts rather directly and suppresses the level of P-450DM/j mainly at a pretranslational step in rat livers.