title: Short communication: insulin alters hepatic progesterone catabolic enzymes cytochrome P450 2C and 3A in dairy cows.
abstract: High proportions of embryonic and early fetal losses in dairy cattle are associated with low peripheral concentrations of progesterone, which could result from increased catabolism, decreased production, or both. Progesterone catabolism occurs primarily in the liver via the cytochrome P450 2C (CYP2C) and cytochrome P450 3A (CYP3A) subfamilies (EC 1.14.14.1; unspecific monooxygenases). Recent observations from our laboratory have shown that the fractional rate constant of progesterone decay can be dramatically reduced by insulin because of a decrease in hepatic CYP2C and CYP3A activity. Little information exists on the regulation of progesterone catabolic enzymes in dairy cows. We hypothesized that elevated insulin concentrations would down-regulate hepatic CYP2C and CYP3A mRNA; therefore, our objectives were to determine the relative abundance of hepatic CYP2C and CYP3A mRNA in dairy cows in response to elevated concentrations of insulin. In the first experiment, 17 mature Holstein cows were drenched daily with 500 mL of water (n = 10) or propylene glycol (a gluconeogenic substrate; n = 7) from 10 d before their expected calving date until d 25 postpartum. Cows drenched with propylene glycol had a 30% increase in peripheral concentrations of insulin. Liver biopsies were collected on d 25 postpartum to determine the relative abundance of CYP2C and CYP3A mRNA. In the second experiment, 19 mature, lactating Holstein cows were randomly assigned to a hyperinsulinemic-euglycemic clamp (0.3 or 1.0 microg of insulin/kg of BW per h; n = 6 each) or remained as controls (saline infused; n = 7) for 96 h beginning on d 10 postpartum. Insulin infusion resulted in a 2.6- or 8- fold increase in peripheral concentrations of insulin, respectively. On d 14 postpartum, a liver biopsy was collected to determine CYP2C and CYP3A mRNA abundance. In experiment 1, the relative abundance of CYP2C mRNA in cows treated with propylene glycol did not differ from controls; however, the relative abundance of CYP3A mRNA in the propylene glycol group was 63% that of controls. For experiment 2, there was a dose-dependent decrease in the relative abundance of both CYP2C and CYP3A mRNA with increasing dosage of insulin. In conclusion, this study demonstrated that, in the cow, either providing a gluconeogenic feed-stuff or treatment with insulin decreased the abundance of mRNA for enzymes responsible for hepatic progesterone catabolism.
authors.affiliation: Division of Animal and Nutritional Sciences, Davis College of Agriculture, Forestry and Consumer Sciences, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: C O
authors.initials: CO
authors.lastname: Lemley
authors.forename: S T
authors.initials: ST
authors.lastname: Butler
authors.forename: W R
authors.initials: WR
authors.lastname: Butler
authors.forename: M E
authors.initials: ME
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001706:Biopsy / Q000662:veterinary; D002417:Cattle / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015309:Glucose Clamp Technique / Q000662:veterinary; D007262:Infusions, Intravenous; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000662:veterinary
chemical_list: D007328:Insulin; D012333:RNA, Messenger; C400322:cytochrome P-450 CYP2C subfamily; D011374:Progesterone; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A