THE SENSITIVITY OF HEPATIC CYP2C GENE-EXPRESSION TO BASE-LINE GROWTH-HORMONE (GH) BIOACTIVITY IN DWARF RATS - EFFECTS OF GH-BINDING PROTEININ-VIVO

Hepatic mRNA transcripts for the steroid-metabolizing enzymes cytochro me P4502C11 (male specific) and P4502C12 (female specific) differ in a bundance by 10- to 20-fold in male and female rats and are regulated b y their different patterns of GH secretion. This sex difference is als o found in;dwarf rats with low GH secretion, implying that these trans cripts may be very sensitive to low level GH exposure. This has now be en characterized in normal and dwarf rats. Continuous iv infusion of r ecombinant human (h) GH (0, 3, 12, and 48 mu g/day) in both dwarf and normal male rats caused a dose-dependent decrease in P4502C11 and an i ncrease in P4502C12, so that the 2C11/2C12 ratio fell from 17.9 +/- 1. 3 to 1.5 +/- 1.0 in normal males and from 6.5 +/- 0.9 to 0.4 +/- 0.3 i n dwarf males (0 vs. 48 mu g hGH/day); over this dose range of hGH, bo dy weight gain, total hepatic insulin-like growth factor-I mRNA levels , and plasma GHBP levels were largely unaffected. These effects of hGH were pattern dependent. The 2C11/2C12 ratio in dwarf males was femini zed (from 11.9 +/- 1.3 to 0.08 +/- 0.03) by continuous infusion of hGH (36 mu g/day), whereas a pulsatile infusion (3-min pulses every 3 h) of the same daily hGH dose was much less effective. Neither continuous nor pulsatile hGH affected P4502C11 or P4502C12 transcripts in dwarf females, although pulsatile hGH infusion caused a significant weight g ain. To test whether baseline GH levels could be modified by circulati ng GH-binding protein (GHBP), hGH infusions were given with and withou t recombinant hGHBP in different patterns. Pulsatile infusions of reco mbinant hGHBP (42 mu g/day, iv) did not prevent the feminizing effect of continuously infused hGH (36 mu g/day, sc) in dwarf males (2C11/2C1 2 ratios were 0.08 +/- 0.01 and 0.09 +/- 0.01 for hGH vs. hGH plus hGH BP, respectively). This suggested that intermittent complex formation with GHBP did not prevent continuous access of hGH to the hepatic GH r eceptors. Furthermore, pulses of hGH complexed with GHBP significantly reduced the 2C11/2C12 ratio in dwarf males (from 21.5 +/- 3.9 with pu lsatile hGH alone to 9.2 +/- 2.5 with pulses of hGH plus hGHBP), indic ating that GHBP prolongs the exposure to hGH. Thus, 2C11/2C12 expressi on is very sensitive to basal GH levels in dwarf rats, and GHBP can al ter hepatic gene expression by modifying the pattern of GH exposure.