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Alterations in Hepatic Enzyme Activity and Progesterone Clearance in Lactating Dairy Cows Caleb Owens Lemley In the cow, inadequate concentrations of progesterone during gestation may lead to an abrupt termination of pregnancy. The primary organ involved in progesterone catabolism is the liver, which contains an abundance of cytochrome P450 isozymes (CYP; EC 1.14.14.1) and aldo-keto reductases (AKR; EC 1.1.1.145-151), which are involved in the first phase of steroid inactivation, before second phase conjugation and excretion of the steroid metabolite by UDP-glucuronosyltransferases (UGT; EC 2.4.1.17). The objectives of the current experiments were to: 1.) determine the effect of feeding two isoenergetic and isonitrogenous diets formulated to cause divergent insulin secretion, on hepatic progesterone catabolic enzyme activity (CYP2C, CYP3A and AKR1C), as well as progesterone clearance, and 2.) determine the relative contributions of CYP2C, CYP3A, AKR1C and UGT enzymes to total progesterone decay in primary bovine hepatic cell cultures. In the first set of experiments, Holstein cows were randomly assigned to either a high cornstarch or a high fiber diet in a cross-over experimental design consisting of two 14 d periods at the WVU animal sciences farm (n = 22) or the NDSU dairy research barn (n = 11). Dry matter intake and milk yield were similar between the two diets. Energy balance was improved in cows consuming the high cornstarch diet. Insulin concentrations were elevated in cows consuming the high cornstarch diet versus the high fiber diet. Both CYP2C and CYP3A activity were decreased in cows consuming the high cornstarch diet, while AKR1C tended to be lower in NDSU cows fed the high cornstarch diet. The half-life of progesterone was longer in cows fed the high cornstarch diet versus the high fiber diet. In NDSU cows, liver blood flow was similar between the two diets (1891 ± 91 l/h), while the metabolic clearance rate of progesterone tended to be lower in cows fed the high cornstarch diet (25 ± 5 l/h*BW) versus the high fiber diet (40 ± 6 l/h*BW). In the second experiment, the contribution of CYP2C and CYP3A enzymes to progesterone inactivation in bovine hepatic cell cultures was 40% and 15%, respectively. Depending on the inhibitor used, it would appear that the aldo-keto reductase enzymes contribute ~ 40% to the observed progesterone decay; although, a portion of this inactivation may be due to the loss of UGT activity. In summary, cows consuming the high cornstarch diet had elevated insulin concentrations, lower hepatic progesterone catabolic enzyme activity and lower progesterone clearance compared to cows consuming the high fiber diet. The majority of progesterone inactivation occurs via hepatic CYP2C, CYP3A and AKR1C activity and inhibiting these enzymes will increase the bioavailability of progesterone. Therefore, feeding diets that stimulate insulin secretion could alter progesterone clearance during lactation by decreasing hepatic progesterone catabolic enzyme activity. This dietary relationship could be used to increase progesterone bioavailability in dairy cows that have increased progesterone clearance due to high-energy demands and elevated dry matter intake. TABLE OF CONTENTS ABSTRACT ii TABLE OF CONTENTS  iii LIST OF FIGURES v LIST OF TABLES  vii ACKNOWLEDGEMENTS  viii REVIEW OF LITERATURE1 Progesterone and Maintenance of Pregnancy 1 Progesterone Biosynthesis  3 Metabolic Clearance of Progesterone  5 Hepatic Catabolic Enzymes and Steroid Biotransformation 8 Nutrition, Energy Balance and Reproductive Performance 12 STATEMENT OF THE PROBLEM 17 EFFECT OF A HIGH CORNSTARCH DIET ON HEPATIC CYTOCHROME P450 2C AND 3A ACTIVITY AND PROGESTERONE HALF-LIFE IN DAIRY COWS 20 Abstract 2

Alterations in hepatic enzyme activity and progesterone clearance in lactating dairy cows