Role of the sulfate transporter SLC26A1 in protection against acetaminophen (Tylenol, Paracetamol) toxicity

Principal Investigator

Scientific interest within the context of the graduate college

Within the graduate college, this project addresses how systemic sulfate homeostasis influences drug-induced liver injury. By studying the role of SLC26A1 in acetaminophen toxicity, it links renal and hepatic physiology with translational and population-based approaches. The integration of mouse models and human biobank data aligns with the program’s goal of bridging basic and clinical research to identify mechanisms and risk factors of acute liver failure.

Project description

Acetaminophen (Tylenol/Paracetamol) toxicity is the leading cause of acute liver failure (ALF) in Western countries. In North America alone, acetaminophen overdose accounts for approximately 50,000 emergency department visits and 500 deaths annually.¹ At therapeutic doses, acetaminophen is primarily metabolized in the liver through glucuronidation and sulfation, resulting in nontoxic conjugates that are efficiently excreted by the kidney.² Sulfation requires the sulfate donor 3′-phosphoadenosine 5′-phosphosulfate (PAPS), whose availability is critically dependent on adequate inorganic sulfate levels.³ SLC26A1 is a major sulfate transporter that our group has studied extensively in both murine models and human populations.^4-6 Prior studies in mice have demonstrated that loss of SLC26A1 function is associated with increased acetaminophen-induced liver injury and elevated transaminase levels.⁷ Although SLC26A1 is highly expressed in the liver, it is also abundantly present in the intestine and kidney. A key unresolved question is whether heightened acetaminophen toxicity associated with impaired SLC26A1 function is driven by reduced systemic sulfate availability (due to renal sulfate wasting) or by impaired local sulfate transport within hepatocytes. We hypothesize that increased acetaminophen toxicity in SLC26A1 deficiency is primarily attributable to reduced plasma sulfate levels resulting from renal sulfate loss, rather than impaired sulfate transport within the liver itself. To test this hypothesis, we will induce acetaminophen-mediated liver injury in mice using an established protocol and compare outcomes across wild-type mice, whole-body SLC26A1 knockout mice, and tissue-specific SLC26A1 knockout models targeting the kidney or liver. In parallel, we have identified approximately 1,400 individuals with damaging SLC26A1 variants within the Mayo Clinic Biobank. We will assess baseline liver function, specifically serum transaminase levels, in these individuals compared with matched controls. Additionally, we will perform Mendelian randomization analyses to determine whether genetic variants in SLC26A1 are associated with higher transaminase levels in the context of acetaminophen exposure. In summary, this proposed doctoral thesis aims to address a critical knowledge gap by integrating mechanistic studies in genetically engineered mouse models, already generated and available, with large-scale, population-based analyses at the Mayo Clinic.

Aim 1: Determine the impact of tissue-specific deletion of SLC26A1 on acetaminophen-induced liver toxicity. This aim will compare acetaminophen toxicity in whole-body SLC26A1 knockout mice versus mice with kidney-and liver-specific deletion of SLC26A1, thereby isolating the contribution of renal sulfate handling.

Aim 2:Evaluate the association between damaging SLC26A1 variants, liver injury markers, and acetaminophen exposure in humans. Using data from the Mayo Clinic Biobank and the Tapestry Study, we will examine whether individuals harboring damaging SLC26A1 variants exhibit higher transaminase levels compared with matched controls, and whether acetaminophen intake further amplifies this association.

Application details

References