Hearing, reactive metabolite formation, and oxidative stress in cochleae after a single acute overdose of acetaminophen: anin vivostudy

Abstract

Context Although the liver is the primary target organ in acetaminophen (APAP) toxicity, other organs are affected. Previous data suggested chronic APAP abuse can be ototoxic and the mechanism involves APAP-induced oxidative stress and reactive metabolite (NAPQI)-induced endoplasmic reticulum stress. However, the effect of a single acute overdose on hearing has not been tested. Objectives To determine if a single acute APAP overdose causes hearing damage, and to explore possible mechanisms of APAP ototoxicity. Materials and Methods Male C57BL/6J mice were treated with a single human-relevant overdose of APAP (300 mg APAP per kg bodyweight). Blood, liver and cochleae were harvested at 0, 2, 6 and 24h post-APAP. In some mice, auditory brainstem responses (ABRs) to a range of frequencies were measured at 24h. The furosemide plus kanamycin (FS/K) model of drug ototoxicity was used as a positive control for hearing loss. NAPQI formation after APAP was assessed by measuring glutathione (GSH) depletion and covalent protein binding, and oxidative stress was assessed by measuring glutathione disulfide (GSSG). Results There was no evidence of reactive metabolite formation or hearing loss after a single overdose of APAP at a clinically relevant dose. However, there was a transient increase in oxidative stress. Discussion Although a single acute overdose was not ototoxic, there was evidence of oxidative stress which may support a role for oxidative stress in hearing loss due to chronic APAP abuse. Conclusion A single human-relevant acute overdose of acetaminophen (APAP) causes transient oxidative stress in cochleae but not hearing loss.

Extrahepatic toxicity of acetaminophen: critical evaluation of the evidence and proposed mechanisms

“…Furthermore, the same group published a more recent study indicating that APAP does not actually cause cell death in HEIOC1 cells, despite evidence of reduced energy metabolism and even increased caspase activity [162]. Finally, a recent in vivo study in mice found no evidence for hearing loss based on auditory brainstem response (ABR) in a clinically relevant model of acute APAP overdose [163]. Thus, it seems unlikely that APAP by itself causes ototoxicity in humans or mice.…”

“…Based on these findings, the authors concluded that APAP and NAPQI exert toxic effects through different mechanisms in cochlear cells: APAP ototoxicity involves oxidative stress and ER stress, while NAPQI causes ER stress without oxidative stress [13]. The only in vivo study of APAP ototoxicity to date also revealed that there is oxidative stress in cochleae after acute APAP overdose [163]; however, no ototoxicity was observed in that study based on auditory brainstem thresholds (ABR) [163].…”

“…Next, it is not known if HEI-CO1 cells, or cochlear cells in general, express P450s at concentrations sufficient to convert APAP to NAPQI. The only study to address that issue revealed that mice treated with a hepatotoxic dose of APAP had no evidence of GSH depletion or protein binding in cochlea [163]. Finally, it is clear that APAP toxicity in vitro does not necessarily translate to toxicity in vivo.…”

Extracts from guava fruit protect renal tubular endothelial cells against acetaminophen‑induced cytotoxicity

“…Furthermore, a recent study suggested that guavas can inhibit caspase activity to attenuate cell apoptosis in type II diabetic rats (32). Because APAP-induced cytotoxicity is related to oxidative stress and caspase activity (13)(14)(15)(16)33,34), and because guavas can inhibit oxidative stress and caspase activity, the present study investigated whether guavas can attenuate APAP-induced renal cytotoxicity.…”

“…Many studies have shown that high doses of APAP can induce cell death through either the apoptotic or necrotic death pathways (10)(11)(12). Previous studies have demonstrated that APAP-induced cytotoxicity is related to increased oxidative stress and glutathione depletion (13)(14)(15)(16). It is well-known that cellular glutathione can convert H 2 O 2 to H 2 O via a glutathione peroxidase reaction to attenuate cellular oxidative stress (17,18).…”