Effects of rGH and G118RrGH on the induction of CYP2C12 and IGF-I in primary rat hepatocytes.
We have investigated the induction of the CYP2C12 and IGF-I genes by rGH and a "binding site 2 mutant", G118RrGH, in primary hepatocytes derived from male and female rats. Both the basal and the induced levels of CYP2C12, but not of IGF-I, were markedly lower in male derived than in female derived hepatocytes. A lower degree of receptor occupancy appears needed to elicit the CYP2C12 than the IGF-I response in cells obtained from both gender. At 7h of GH exposure high doses of rGH caused a bell-shaped induction of IGF-1 and a plateau was reached for CYP2C12 in female derived cells. G118RrGH did not antagonize the rGH effect; in contrast G118RrGH had an agonistic effect on CYP2C12 induction in female derived cells that in dose-response experiments was bell-shaped. The difficulty in achieving bell-shaped dose-response curves with rGH, together with the lack of an antagonistic effect of G118RrGH, suggests that both binding sites of rGH have similar affinity for the rGHR. The agonistic and bell-shaped dose-related effect of G118RrGH on CYP2C12 expression indicates that G118RrGH interacts with two receptors. The results could also imply that rGH, via its site 2, can interact with other receptor molecules than rGHR.
Helander
Hanna
H
Department of Medical Nutrition, Karolinska Institutet, Novum, Huddinge S-141 86, Sweden.
Clark
Ross G
RG
Mode
Agneta
A
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D013006:Growth Hormone / Q000235:genetics / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis*; D008297:Male; D017354:Point Mutation; D051381:Rats; D013250:Steroid Hydroxylases / Q000096:biosynthesis*; D013997:Time Factors; D015854:Up-Regulation
D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C034694:steroid 15-beta-hydroxylase