Downregulation of Sulfotransferase Expression and Activity in Diseased Human Livers

Yalçın, Emine; More, Vijay R.; Neira, Karissa L; Lu, Zhenqiang; Cherrington, Nathan J.; Slitt, Angela L.; King, Roberta S.

doi:10.1124/dmd.113.050930

Cited by 48 publications

(43 citation statements)

References 57 publications

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“…These results are also in parallel with previous data demonstrating decreased pan-sulfotransferase activity in NASH despite the protein induction of several sulfotransferase isoforms in the disease (Hardwick et al, 2013). Moreover, decreased total sulfotransferase activity in humans with alcoholic and nonalcoholic liver disease was identified in an independent study (Yalcin et al, 2013). Together, these results are suggestive of disrupted cellular sulfur activation and utilization in NASH, which would ultimately limit the intracellular concentrations of the sulfonation cofactor, 39-phosphoadenosine-53-phosphosulfate (PAPS).…”

Section: Discussionsupporting

confidence: 91%

Altered Regulation of Hepatic Efflux Transporters Disrupts Acetaminophen Disposition in Pediatric Nonalcoholic Steatohepatitis

et al. 2015

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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, representing a spectrum of liver pathologies that include simple hepatic steatosis and the more advanced nonalcoholic steatohepatitis (NASH). The current study was conducted to determine whether pediatric NASH also results in altered disposition of acetaminophen (APAP) and its two primary metabolites, APAP-sulfate and APAP-glucuronide. Pediatric patients with hepatic steatosis (n = 9) or NASH (n = 3) and healthy patients (n = 12) were recruited in a small pilot study design. All patients received a single 1000-mg dose of APAP. Blood and urine samples were collected at 1, 2, and 4 hours postdose, and APAP and APAP metabolites were determined by high-performance liquid chromatography. Moreover, human liver tissues from patients diagnosed with various stages of NAFLD were acquired from the Liver Tissue Cell Distribution System to investigate the regulation of the membrane transporters, multidrug resistanceassociated protein 2 and 3 (MRP2 and MRP3, respectively). Patients with the more severe disease (i.e., NASH) had increased serum and urinary levels of APAP-glucuronide along with decreased serum levels of APAP-sulfate. Moreover, an induction of hepatic MRP3 and altered canalicular localization of the biliary efflux transporter, MRP2, describes the likely mechanism for the observed increase in plasma retention of APAP-glucuronide, whereas altered regulation of sulfur activation genes may explain decreased sulfonation activity in NASH. APAP-glucuronide and APAP-sulfate disposition is altered in NASH and is likely due to hepatic membrane transporter dysregulation as well as altered intracellular sulfur activation.

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Section: Discussionsupporting

confidence: 91%

Altered Regulation of Hepatic Efflux Transporters Disrupts Acetaminophen Disposition in Pediatric Nonalcoholic Steatohepatitis

et al. 2015

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“…In human patients, SULT1A2 was found to be down-regulated in NASH (Younossi et al , 2005); and resulted in decreased plasma levels of acetaminophen-sulfate (Canet et al , 2015). Yalcin and colleagues (Yalcin et al , 2013) also observed that sulfotransferase activity decreased significantly with severity of liver disease from steatosis to cirrhosis. Available reports therefore suggest that the activities of SULT1A1 and SULT1A3 were lower in disease states compared to non-steatotic tissues.…”

Section: Introductionmentioning

confidence: 93%

Non-alcoholic fatty liver disease (NAFLD) – pathogenesis, classification, and effect on drug metabolizing enzymes and transporters

Cobbina

Akhlaghi

2017

Drug Metabolism Reviews

477

351

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Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5 % of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a ‘three-hit’ process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 have been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may results in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters. Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 are more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 are up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major drug metabolizing enzymes and transporters. We also discuss the potential mechanisms underlying these alterations.

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“…The extremely broad specificity of SULT1A1 enables it to sulfonate the scores of small molecules-both endogenous metabolites and xenobiotics-needed to perform its homoeostatic and detoxicating functions. Imbalances in these functions have been linked to numerous diseases, including breast (Falany et al, 2002) and endometrial (Falany and Falany, 1996) cancer, Parkinson disease (Steventon et al, 1989), cystic fibrosis (Li and Falany, 2007), diabetes (Yalcin et al, 2013), and hemophilia (Moore, 2003).…”

Section: Introductionmentioning

confidence: 99%

Design and Interpretation of Human Sulfotransferase A1 Assays

Wang

Cook

Leyh

2015

Drug Metabolism and Disposition

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The human sulfotransferases (SULTs) regulate the activities of hundreds, if not thousands, of small molecule metabolites via transfer of the sulfuryl-moiety (-SO 3 ) from the nucleotide donor, 39-phosphoadenosine 59-phosphosulfate (PAPS) to the hydroxyls and amines of the recipients. Our understanding of the molecular basis of SULT catalysis has expanded considerably in recent years. The basic kinetic mechanism of these enzymes, previously thought to be ordered, has been redefined as random for SULT2A1, a representative member of the superfamily. An active-site cap whose structure and dynamics are highly responsive to nucleotides was discovered and shown to be critical in determining SULT selectivity, a topic of longstanding interest to the field. We now realize that a given SULT can operate in two specificity modes-broad and narrow-depending on the disposition of the cap. More recent work has revealed that the caps of the SULT1A1 are controlled by homotropic allosteric interactions between PAPS molecules bound at the dimer's active sites. These interactions cause the catalytic efficiency of SULT1A1 to vary in a substrate-dependent fashion by as much as two orders of magnitude over a range of PAPS concentrations that spans those found in human tissues. SULT catalysis is further complicated by the fact that these enzymes are frequently inhibited by their substrates. This review provides an overview of the mechanistic features of SULT1A1 that are important for the design and interpretation of SULT1A1 assays.

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Downregulation of Sulfotransferase Expression and Activity in Diseased Human Livers

Abstract: Sulfotransferase (SULT) function has been well studied in healthy human subjects by quantifying mRNA and protein expression and determining enzyme activity with probe substrates.

Cited by 48 publications

References 57 publications

Altered Regulation of Hepatic Efflux Transporters Disrupts Acetaminophen Disposition in Pediatric Nonalcoholic Steatohepatitis

Altered Regulation of Hepatic Efflux Transporters Disrupts Acetaminophen Disposition in Pediatric Nonalcoholic Steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) – pathogenesis, classification, and effect on drug metabolizing enzymes and transporters

Design and Interpretation of Human Sulfotransferase A1 Assays

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