University of Louisville

Poster Title

Therapeutic Interventions in Toxicant-Associated Steatohepatitis

Institution

University of Louisville

Abstract

Toxicant-Associated Steatohepatitis (TASH) is a non-alcoholic fatty liver disease observed with greater than 80% incidence in heavily exposed vinyl chloride (VC) workers. VC toxicity requires CYP2E1- dependent metabolism to chloroethylene oxide, which rapidly breaks down to chloroacetaldehyde (ClAc). ClAc is a thiol reactive aldehyde that adducts cellular proteins. ClAc disrupts mitochondrial function leading to depleted ATP levels with consequent necrotic cell death. Our hypothesis is that therapy that increases glutathione concentration and ClAc detoxication will protect against protein adduction and mitochondrial dysfunction. We propose to utilize two model nrf-2-dependent gene transcription inducers, sulforaphane and oltipraz in a HepG2 cell based system. Treatment with either sulforaphane or oltipraz increased glutathione levels, NAD(P)H:quinone oxidoreductase activity, and nrf-2 response element containing reporter activity. The LD50 for ChlAc (100.368 ± 1.217 µM) was increased by pretreatment with either sulforaphane (136.128 ± 2.070 µM) or oltipraz (113.430 ± 2.036 µM). Both ATP and glutathione levels in all groups are decreased following ClAc treatment; however cells pretreated with either sulforaphane or oltipraz had higher levels of ATP and glutathione at 1–h and 4-h, respectively. Both sulforaphane and oltipraz protected cells against ClAc-dependent inhibition of mitochondrial respiration measured using a Seahorse XF24 Extracellular Flux Analyzer. Sulforaphane and oltipraz reduced the ability of ClAc to inhibit oxygen consumption and oxidative reserve capacity. In conclusion, nrf-2 inducers are an effective mechanism based therapy for ClAc toxicity and potentially VC-induced TASH. Supported by NIH grants P20RR024489, 5P30ES014443, 1P01AA017103, and RC2AA019385.

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Therapeutic Interventions in Toxicant-Associated Steatohepatitis

Toxicant-Associated Steatohepatitis (TASH) is a non-alcoholic fatty liver disease observed with greater than 80% incidence in heavily exposed vinyl chloride (VC) workers. VC toxicity requires CYP2E1- dependent metabolism to chloroethylene oxide, which rapidly breaks down to chloroacetaldehyde (ClAc). ClAc is a thiol reactive aldehyde that adducts cellular proteins. ClAc disrupts mitochondrial function leading to depleted ATP levels with consequent necrotic cell death. Our hypothesis is that therapy that increases glutathione concentration and ClAc detoxication will protect against protein adduction and mitochondrial dysfunction. We propose to utilize two model nrf-2-dependent gene transcription inducers, sulforaphane and oltipraz in a HepG2 cell based system. Treatment with either sulforaphane or oltipraz increased glutathione levels, NAD(P)H:quinone oxidoreductase activity, and nrf-2 response element containing reporter activity. The LD50 for ChlAc (100.368 ± 1.217 µM) was increased by pretreatment with either sulforaphane (136.128 ± 2.070 µM) or oltipraz (113.430 ± 2.036 µM). Both ATP and glutathione levels in all groups are decreased following ClAc treatment; however cells pretreated with either sulforaphane or oltipraz had higher levels of ATP and glutathione at 1–h and 4-h, respectively. Both sulforaphane and oltipraz protected cells against ClAc-dependent inhibition of mitochondrial respiration measured using a Seahorse XF24 Extracellular Flux Analyzer. Sulforaphane and oltipraz reduced the ability of ClAc to inhibit oxygen consumption and oxidative reserve capacity. In conclusion, nrf-2 inducers are an effective mechanism based therapy for ClAc toxicity and potentially VC-induced TASH. Supported by NIH grants P20RR024489, 5P30ES014443, 1P01AA017103, and RC2AA019385.