The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

Abstract

Endogenous factors, including hormones, growth factors and cytokines, play an important role in the regulation of hepatic drug metabolizing enzyme expression in both physiological and pathophysiological conditions. Alterations of hepatic drug metabolizing enzymes gene and protein expression, observed in diabetes, fasting, obesity, protein-calorie malnutrition and long-term alcohol consumption alters the metabolism of xenobiotics, including procarcinogens, carcinogens, toxicants, and therapeutic agents and may also impact the efficacy and safety of therapeutic agents, as well as result in drug-drug interactions. Although the mechanisms by which xenobiotics regulate drug metabolizing enzymes have been studied intensively, less is known regarding the cellular signaling pathways and components which regulate drug metabolizing enzyme gene and protein expression in response to hormones and cytokines. Recent findings, however, have revealed that several cellular signaling pathways are involved in hormone-and growth factor-mediated regulation of drug metabolizing enzymes. Our laboratory, and others, have demonstrated that insulin and growth factors regulate drug metabolizing enzyme gene and protein expression, including cytochromes P450, glutathione S-transferases and microsomal epoxide hydrolase, through receptors which are members of the large receptor tyrosine kinase family, and by downstream effectors such as phosphatidylinositol 3-kinase, the mitogen activated protein kinase, Akt/protein kinase B, mTOR, and the p70S6 kinase. Here, we review current knowledge of the signaling pathways implicated in regulation of drug metabolizing enzyme gene and protein expression in response to insulin and growth factors, with the goal of increasing our understanding of how chronic disease affects these signaling pathways, components, and ultimately gene expression and translational control.

Liquid fructose down-regulates liver insulin receptor substrate 2 and gluconeogenic enzymes by modifying nutrient sensing factors in rats

“…We also found 5 that fructose-fed female rats displayed a significantly reduced expression of liver insulin-related substrate-2 (IRS-2) [17], one of the key insulin-signaling proteins in the liver [25].…”

Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction

“…A variety of environmental carcinogens, including low levels of UV-B irradiation, also activate Nrf2 and up-regulate AREresponsive gene products to enhance protection against cellular and molecular damage that can induce cancer (17). In addition, changes in insulin levels during fasting induce a mild oxidative stress and an alteration of the expression of Nrf2-induced enzymes (18).…”

Kinases and glutathione transferases: selective and sensitive targeting

“…It was also shown that the insulin-mediated increase in GST A protein levels in hepatocytes is independent of MEK1 inhibition that lead to ERK1/2 pathway blockage, in addition to p38 MAPK, HSP27 and PKC inhibition in hepatocytes (Kim et al, 2006). Consequently, PI3K/Akt/p70S6K signaling was determined functioning in the insulin-mediated upregulation of the antioxidant defense system, and potentially enhances the hepatocytes susceptibility to xenobiotic-or oxidative stressmediated damage (Kim and Novak, 2007).…”