Interaction Between the Liver Disease Nonalcoholic Steatohepatitis and the Ubiquitous Cyanotoxin Microcystin-LR Found in Drinking Water Around the World

Dr. John Clarke received SWEHSC pilot project and career development funds to collect preliminary data for his K99/R00 application to the NIEHS and to facilitate professional development activities. MCLR exposure is well documented to cause hepatic and renal toxicities. The overlap between this at-risk population (NASH patients) and MCLR exposure is anticipated to impact millions of people worldwide because of the current and increasing incidence of NASH and cyanotoxin producing blooms. Although this overlap is certain to occur, there is a paucity of information regarding how NASH affects MCLR metabolism, disposition, and toxicity. Dr. Clarke accumulated NASH-specific data to show that the disease alters the expression of the hepatic uptake transporters, organic anion transporting polypeptides (OATPs), and increases systemic exposure of multiple OATP substrates in rodents. His hypothesis states that these NASH-specific changes in OATP transporters will cause increased systemic exposure to MCLR and increased renal toxicity. This hypothesis will be tested by 1) providing a complete picture of the transporters involved in MCLR disposition, 2) determining the disposition of MCLR and its metabolites in the context of NASH, 3) determining the toxicity of acute and sub-chronic MCLR exposure in NASH, and 4) developing a physiology based toxicokinetics (PBTK) model for human exposure to MCLR in the context of NASH. The pilot project funds were specifically used to perform a preliminary MCLR dose-response study and the data from that preliminary study clearly support the hypothesis and were included in his resubmission of the K99/R00 application.  The resubmission scored well and funding of this application is pending council review.