Growth hormone and vitamin A induce P4502C7 mRNA expression in primary rat hepatocytes

The effects of growth hormone (GH) and retinoids on P4502C7 mRNA levels were investigated in cultured primary hepatocytes from normal female rats. Northern blot analysis of total nucleic acids from hepatocytes maintained in culture for 90 hr showed low basal levels of P4502C7 mRNA, which were marginally increased after continuous treatment with GH. Retinal treatment gave a slightly higher induction than GH, whereas treatment with all-trans retinoic acid alone or with GH in combination with retinol induced P4502C7 mRNA to levels about one-third of those in normal female rat liver. The effects of retinoids on P4502C7 mRNA were dependent on both the dose and type of retinoid used. All-trans retinoic acid produced a saturable dose-response curve with a 50% maximal induction of P4502C7 mRNA at 1.5 microM. The isomer 9-cis retinoic acid showed a dose-dependent activation of P4502C7 mRNA similar to that of all-trans retinoic acid. Retinol gave a 50% maximal response at approximately 5 microM. In the presence of GH, the induction of P4502C7 mRNA appeared additive to the effect of retinol at all concentrations used and to all-trans retinoic acid at concentrations up to 1 microM. As determined by a quantitative solution hybridization assay, P4502C7 mRNA levels were induced 3-fold by GH, 5-fold by retinol, and 19-fold by all-trans retinoic acid. In the presence of GH, P4502C7 was induced 8-fold by retinol, whereas the induction by saturating concentration of all-trans retinoic acid showed no significant additional effect of GH. The importance of vitamin A for the expression of P4502C7 in vivo was confirmed by the low abundance of P4502C7 mRNA in vitamin A-deficient animals as compared with vitamin A-adequate control rats. Nuclear run-on experiments performed in cultured primary hepatocytes showed that both GH and retinoic acid exert their effects at the transcriptional level. We conclude that both GH and retinoids can induce P4502C7 mRNA in rat liver hepatocytes, retinoic acid being the dominant inducer.