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Developmental Expression of the Cytosolic Sulfotransferases in Human Liver
Citation:
Dubaisi, S., J. Caruso, R. Gaedigk, C. Vyhlidal, P. Smith, R. Hines, T. Kocarek, AND M. Runge-Morris. Developmental Expression of the Cytosolic Sulfotransferases in Human Liver. DRUG METABOLISM AND DISPOSITION. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD, 47(6):592-600, (2019). https://doi.org/10.1124/dmd.119.086363
Impact/Purpose:
Experimental and epidemiological studies increasingly indicate that early life exposures to environmental stressors can increase a person’s risk for developing diseases, such as cancer and metabolic syndrome, later in life. The vulnerability of a developing fetus to the adverse effects of xenobiotic exposures is modulated by the defense systems that are present in mother and child. It is well known that xenobiotic-metabolizing enzymes and transporters that contribute substantially to that defense system undergo temporal-dependent changes in expression during development. Three major patterns of hepatic expression during development have been described: (1) class I, where expression is highest in prenatal liver, (2) class II, where expression is relatively constant from prenatal to adult life, and (3) class III, where expression is highest in adult liver. The cytosolic sulfotransferases (SULTs) are xenobiotic-metabolizing enzymes that add a sulfonate moiety to a suitable functional group on a substrate molecule. These conjugation reactions protect against toxicity produced by certain chemicals. A previous study reported that SULT1E1, 1A1, and 2A1 proteins are expressed with class I, II, and III developmental patterns, respectively. The current study is the first to evaluate the ontogeny of all major human hepatic SULT enzymes. To optimize rigor, expression was evaluated at both the RNA and protein level with three independent sets of human liver specimens and three different methods of measurement.
Description:
The liver is the predominant organ of metabolism for many endogenous and foreign chemicals. Cytosolic sulfotransferases (SULTs) catalyze the sulfonation of drugs and other xenobiotics, as well as hormones, neurotransmitters, and sterols, with consequences that include enhanced drug elimination, hormone inactivation, and pro-carcinogen bioactivation. SULTs are classified into six gene families, but only SULT1 and SULT2 enzymes are expressed in human liver. We characterized the developmental expression patterns of SULT1 and SULT2 mRNAs and proteins in human liver samples using quantitative RT-PCR (RT-qPCR), RNA sequencing, and targeted quantitative proteomics. Using a set of prenatal, infant, and adult liver specimens, RTqPCR analysis demonstrated that SULT1A1 (transcript variant 1) expression did not vary appreciably during development; SULT1C2, 1C4, and 1E1 mRNA levels were highest in prenatal and/or infant liver; and 1A2, 1B1, and 2A1 mRNA levels were highest in infant and/or adult. Hepatic SULT1A1 (transcript variant 5), 1C3, and 2B1 mRNA levels were low regardless of developmental stage. RNA sequencing of a different set of liver specimens (prenatal and pediatric) provided generally comparable results to those of the RT-qPCR analysis, with the additional finding that SULT1A3 expression was highest during gestation. Analysis of SULT protein content in a library of human liver cytosols demonstrated that protein levels generally corresponded with the mRNAs, with the major exception that SULT1C4 protein levels were much lower than expected based on mRNA levels. These findings further support the concept that hepatic SULTs play important metabolic roles throughout the human life-course, including early development.
