Biol. Pharm. Bull. 28(1) 143—147 (2005)

parenteral hyperalimentation, all of the patient’s daily nutritional requirements are supplied by infusing nutrients directly into the systemic circulation. TPN is widely employed in a variety of pathophysiological settings for the nutritional support of patients with conditions requiring complete bowel rest (e.g., some stages of Crohn’s disease, ulcerative colitis, and severe pancreatitis) or pediatric patients with gastrointestinal disorders (e.g., congenital anomalies and protracted nonspecific diarrhea). In particular, TPN therapy is essential for low-birth-weight neonates and infants with inflammatory bowel disease or Crohn’s disease. However, it has been recognized that the excessive administration of fat-free TPN is associated with the development of cholestasis and hepatic steatosis, which can be fatal in neonates or infants who do not receive oral feeding for a prolonged period. In addition to such pathophysiological abnormalities, hepatic drug metabolizing activity is markedly affected by fat-free TPN in humans and rats. Knodell et al. reported that 7-d parenteral infusion of a hyperalimentation solution containing glucose, amino acids, and electrolytes via the jugular vein led to a decrease in cytochrome P450-mediated oxidative metabolism in rats. Thus, TPN therapy without fat may affect the pharmacokinetics of therapeutic drugs and eventually induce adverse events in patients. The hepatic cytochrome P450 (CYP) isoenzymes are involved in the detoxification of endogenous and exogenous compounds for further metabolism or elimination. Therapeutic drugs are mainly metabolized by the CYP1, CYP2, and CYP3 isoenzymes in the CYP families. The CYP4 family has been shown to be related to the metabolism of fatty acids. Since the capacity of CYP-mediated drug metabolism in the neonate or infant is lower than that in the adult, severe adverse reactions may occur in pediatric patients if additional pharmacotherapy is required during fat-free TPN therapy. It is therefore important to elucidate the specific changes in the hepatic CYP isoenzymes during fat-free TPN in the neonate or infant and to clarify the effects of including fat in the TPN regimen. However, to the best of our knowledge, there have been no reports in the literature focusing on the changes in hepatic CYP isoenzymes during TPN therapy. Intravenous fat emulsions, especially soybean oil, are now available as a source of essential fatty acids in patients receiving TPN, and “three-in-one” solutions containing a mixture of amino acids, glucose, and lipid have been found to be clinically safe, stable, and economical. However, there has been some controversy regarding the possible advantages of including fat in the TPN regimen. Some studies have found that intravenous fat infusion can improve hepatic dysfunction, but others have reported that it may induce hepatic steatosis and progressive cholestasis in humans and rats. We have recently developed an infant rat model of hepatic dysfunction and steatosis induced by overdose of fat-free TPN. Using this animal model, we have demonstrated that metabolic complications such as those related to fat in the liver can be significantly improved by including fat in the TPN regimen. In the present study, we therefore focused on investigating the changes in the mRNA expression of hepatic CYP isoenzymes in this infant rat model following the administration of TPN with or without soybean oil emulsion. The high-sensitivity real-time reverse transcription-polymerase chain reaction (RT-PCR) method with newly designed probes was employed. In this paper, we present the first report that the administration TPN without fat induced marked and selective down-regulation of hepatic CYP mRNAs in the infant rat and that the addition of soybean oil emulsion to the TPN regimen dramatically reduced the down-regulation of CYP mRNAs and prevented the development of hepatic dysfunction. January 2005 Biol. Pharm. Bull. 28(1) 143—147 (2005) 143