Ferroptosis is Involved in Acetaminophen Induced Cell Death

Abstract

The recently described form of programmed cell death, ferroptosis can be induced by agents causing GSH depletion or the inhibition of GPX4. Ferroptosis clearly shows distinct morphologic, biochemical and genetic features from apoptosis, necrosis and autophagy. Since NAPQI the highly reactive metabolite of the widely applied analgesic and antipyretic, acetaminophen induces a cell death which can be characterized by GSH depletion, GPX inhibition and caspase independency the involvement of ferroptosis in acetaminophen induced cell death has been investigated. The specific ferroptosis inhibitor ferrostatin-1 failed to elevate the viability of acetaminophen treated HepG2 cells. It should be noticed that these cells do not form NAPQI due to the lack of phase I enzyme expression therefore GSH depletion cannot be observed. However in the case of acetaminophen treated primary mouse hepatocytes the significant elevation of cell viability could be observed upon ferrostatin-1 treatment. Similar to ferrostatin-1 treatment, the addition of the RIP1 kinase inhibitor necrostatin-1 could also elevate the viability of acetaminophen treated primary hepatocytes. Ferrostatin-1 has no influence on the expression of CYP2E1 or on the cellular GSH level which suggest that the protective effect of ferrostatin-1 in APAP induced cell death is not based on the reduced metabolism of APAP to NAPQI or on altered NAPQI conjugation by cellular GSH. Our results suggest that beyond necroptosis and apoptosis a third programmed cell death, ferroptosis is also involved in acetaminophen induced cell death in primary hepatocytes.

Ferroptosis: process and function

“…In addition to necrosis and apoptosis, acetaminophen induces ferroptosis in primary mouse hepatocytes, but not in HepG2 liver cancer cell lines. 8 The protective effect of ferrostatin-1 against acetaminophen-induced cell death does not occur from the reduced metabolism of acetaminophen or GSH depletion. 8 FIN.…”

“…8 The protective effect of ferrostatin-1 against acetaminophen-induced cell death does not occur from the reduced metabolism of acetaminophen or GSH depletion. 8 FIN. In a larger screening to find ferroptosis-inducing compounds, a series of small molecule inducers, namely ferroptosis-inducing agents (FINs), were discovered.…”

“…Acetaminophen has been demonstrated to induce ferroptosis in primary liver cells and ferroptosis inhibitors such as ferrostain-1 can inhibit acetaminophen-induced death. 8 Ferroptosis is also implicated in hepatic ischemic damage in mice. Ischemia/ reperfusion-induced liver injury can be ameliorated in mice by the ferroptosis inhibitor liproxstatin-1.…”

Vízoldaható antioxidánsok döntéshelyzetben

“…APAP kezelés hatására jelentõs mértékben megnövekedett az apoptotikus sejtek száma, azonban a nekrózis mennyiségileg jóval jelentõsebb mértékû volt 26 . Ezt követõen kimutattuk, hogy a nekroptózis és az apoptózis mellett egy harmadik programozott sejthalál típus, a ferroptózis is szerepet kap az APAP kiváltotta sejthalál folyamatában primer egér májsejtekben 27 . Eredményeink alapján a ferroptózis gátlószer, ferrostatin-1 védõhatása, nem a csökkent APAP-NAPQI metabolizmusból és nem a megváltozott GSH-val történõ NAPQI konjugációból fakad.…”

“…Az APAP kiváltotta sejthalál folyamatát gátolta a C-és E-vitamin. A C-vitamin, valamint a C-és E-vitamin kombinációjának védõhatása meghaladta a kizárólag önmagában adagolt E-vitaminét 27 .…”