Impact of metabolic and liver disease on cytosolic sulfotransferase expression and activity
The rise in metabolic syndrome is one of the main growing concerns in the developing world since it is estimated to be diagnosed in one third of adults (20 years of age and over) in the United States. Metabolic syndrome has been identified as a factor that may increase the risk of cardiovascular disease and requires having three or more risk factors in an adult including abdominal obesity, high triglyceride, low HDL cholesterol, high blood pressure, and high fasting glucose levels. Nonalcoholic fatty liver disease (NAFLD) is the hepatic compartment of metabolic syndrome, thus characterized as the accumulation of fat in liver in the absence of excessive alcohol intake. The pathology of metabolic syndrome accommodates a complex network including multiple signaling pathways eventually leading to alterations in hepatic gene expression at mRNA and protein levels thus causing altered activity and function in animal models. Drug-metabolizing enzymes play a vital role in the elimination of xenobiotics such as drugs or environmental compounds. In addition, they are involved in the homeostasis of endogenous molecules such as hormones, bile acids or neurotransmitters. Liver is the major organ involved in the metabolism of these exogenous and endogenous molecules. The alterations in drug metabolizing enzyme activity due to metabolic syndrome may affect the clearance of therapeutic drugs, potentially resulting in adverse drug interactions. Due to the increased retention time of the potentially harmful compound,individuals may have a longer exposure to the compound, which may lead to toxicity. The homeostasis of endogenous chemicals also has been found to be affected by the altered levels of metabolism enzymes during metabolic syndrome. The physiological concentrations of steroid hormones, neurotransmitters, bile acids have been detected to be altered in diseased livers. Sulfotransferases are one of the main regulators involved in the biotransformation of these exogenous and endogenous molecules. Our aim is to characterize the hepatic expression and sulfonation capability of this phase II metabolism enzyme family in livers diagnosed with a component of metabolic disease. The initial study reported in chapter three investigates the impact of nonalcoholic fatty liver disease (NAFLD) and alcohol cirrhosis on hepatic sulfotransferases in humans. Sulfotransferase expression and activity decreased significantly with severity of liver disease from steatosis to cirrhosis. SULT1A1 and SULT1A3 activities were progressively lower in disease states relative to non-fatty tissues. Alcoholic cirrhotic tissues further contained lower SULT1A1 and 1A3 activities than either of the two other disease states. SULT2A1, on the other hand, was only reduced in alcoholic cirrhotic tissues. SULT1E1 was reduced in both diabetic cirrhosis and alcoholic cirrhosis tissues, relative to nonfatty liver tissues. The second study presented in the second chapter determined the expression levels and sulfonation capability of major hepatic sulfotransferases in wild type and genetically modified obese mouse models under fed ad libitum,fasted, or calorie restricted conditions. Obesity induced Sult2a1 and Sult1e1, while suppressing Sult1a1 levels. Fasting showed inductive effects on Sult1a1 and Sult1d1. The third study presented in chapter four includes the sulfonation of bisphenol A (BPA), a widely used industrial chemical known as an endocrine disruptor to which humans are regularly exposed. Through glucuronidation and sulfonation, liver metabolizes and facilitates excretion of BPA. Sulfonation of BPA has been reported in primary hepatocytes; several SULT-enzymes efficiently catalyze BPA-sulfate, and BPA-sulfate is a human urinary metabolite of BPA. Therefore, even though being a minor pathway, BPA sulfonation is also expected to efficiently detoxify BPA. We found a dramatic decrease in BPA sulfonation in individuals diagnosed with steatosis, diabetes, and cirrhosis as compared to nonfatty livers indicating that BPA clearance may be decreased in diseased livers. As detected in BPA metabolism, the altered levels of sulfotransferase expression and activity in diseased versus non-diseased liver tissue may affect the metabolism and disposition of many other xenobiotics and homeostasis of endobiotics. This might be a consequence of damaged tissue, but may lead to other cellular events such as xenobiotic accumulation and toxicity due to diminished SULT1A1, alteration in androgen synthesis and metabolism due to modified SULT2A1, alteration in estrogen metabolism due to modified SULT1E1, or accumulation of catecholamines due to diminished SULT1A3 levels in diseased liver.
Emine Bihter Yalcin,
"Impact of metabolic and liver disease on cytosolic sulfotransferase expression and activity"
Dissertations and Master's Theses (Campus Access).