In Vivo Mechanisms of Tissue-Selective Drug Toxicity: Effects of Liver-Specific Knockout of the NADPH-Cytochrome P450 Reductase Gene on Acetaminophen Toxicity in Kidney, Lung, and Nasal Mucosa

Gu, Jun; Cui, Huadong; Behr, Melissa; Zhang, Li; Zhang, Qing Yu; Yang, Weizhu; Hinson, Jack; Ding, Xinxin

doi:10.1124/mol.104.007898

Cited by 101 publications

(87 citation statements)

References 30 publications

(31 reference statements)

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“…The primary toxicity of APAP is the result of drug metabolism in both the liver and extra hepatic tissues (Gu et al, 2005). At therapeutic doses, APAP is metabolized via glucuronidation and sulfation reactions occurring primarily in the liver which result in the water-soluble metabolites that are excreted via the kidney.…”

Section: Discussionmentioning

confidence: 99%

Acetaminophen Induced Kidney Failure in Rats: A Dose Response Study

Roy¹,

Pradhan²,

Das³

et al. 2015

J. of Biological Sciences

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A B S T R A C TAcetaminophen is a commonly used analgesic and antipyretic drug, high doses of which cause hepatic and renal injury. In development and progression of kidney disease research, it is necessary to have a suitable common drug to induce uremia and renal failure of rats. It is also required to select the threshold doses for the said drug; a therapeutic dose and toxic dose for kidney failure using standard guidelines. An acute toxicity of acetaminophen was conducted by the limit test at a dose of 2000 mg kgG 1 b.wt., on either sex rats (n = 5) and a main test was conducted by a dose progression factor of 3.2 times as per Organization of Economic Co-Operation and Development guidelines 425. Eighteen male albino rats (n = 18) were divided into three groups, group I served as control, groups II and III rats were administered 175 mg and 550 mg kgG 1 b.wt., acetaminophen intraperitoneally for 14 days, respectively. Different parameters were considered to analyze renal failure. Urea, creatinine, GOT, GPT and MDA levels were increased significantly (p<0.05) in group III, compared to groups I and II. Antioxidant enzymes like SOD, catalase and GSH level were decreased significantly (p<0.05) in group III rats, compared to group I and II rats. Increase in blood uremia profile indicated that the higher dose of acetaminophen causes uremia. Increase in the toxicity markers and lipid peroxidation marker enzymes indicate the nephrotoxicity. Histological structures of kidney of group III animals showed a severe disorganization of glomerulus and dilation of renal tubules. These results indicate that intraperitoneal injection of acetaminophen at high dose causes nephrotoxicity and renal cellular damage to experimental rats.

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Section: Discussionmentioning

confidence: 99%

Acetaminophen Induced Kidney Failure in Rats: A Dose Response Study

Roy¹,

Pradhan²,

Das³

et al. 2015

J. of Biological Sciences

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“…The primary toxicity of acetaminophen is the result of drug metabolism in both the liver and extrahepatic tissues [5]. Only 1% of the drug is excreted unchanged in the urine.…”

Section: Pharmacology/pathophysiologymentioning

confidence: 99%

Acetaminophen-induced nephrotoxicity: Pathophysiology, clinical manifestations, and management

2008

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Acetaminophen-induced liver necrosis has been studied extensively, but the extrahepatic manifestations of acetaminophen toxicity are currently not described well in the literature. Renal insufficiency occurs in approximately 1-2% of patients with acetaminophen overdose. The pathophysiology of renal toxicity in acetaminophen poisoning has been attributed to cytochrome P-450 mixed function oxidase isoenzymes present in the kidney, although other mechanisms have been elucidated, including the role of prostaglandin synthetase and N-deacetylase enzymes. Paradoxically, glutathione is considered an important element in the detoxification of acetaminophen and its metabolites; however, its conjugates have been implicated in the formation of nephrotoxic compounds. Acetaminophen-induced renal failure becomes evident after hepatotoxicity in most cases, but can be differentiated from the hepatorenal syndrome, which may complicate fulminant hepatic failure. The role of N-acetylcysteine therapy in the setting of acetaminophen-induced renal failure is unclear. This review will focus on the pathophysiology, clinical features, and management of renal insufficiency in the setting of acute acetaminophen toxicity.Case: A 47-year-old female was found lethargic at home and brought by ambulance to an emergency department. History from family members suggested an inadvertent acetaminophen overdose, and she had last been seen a few hours earlier. She reportedly ingested 18 tablets of 500 mg acetaminophen (APAP) over the previous two days because she had run out of her prescription pain medication. Her past medical history was significant for fibromyalgia, arthritis, and a prior gastric bypass procedure. She had no history of alcohol abuse or renal insufficiency. She was lethargic. Vital signs: BP 128/96 mmHg, pulse 112/min, respirations 32/min; pulse oximetry 98% on 2L nasal cannula oxygen. Laboratory studies: BUN 9 mg/dL, creatinine 0.9 mg/dl, acetaminophen 12 mcg/mL, AST 5409 u/L and ALT 1085 u/L. A urinalysis was negative for blood with trace protein and ketones. A urine drug screen was positive for marijuana and opioid metabolites. At the initial hospital, she was treated with N-acetylcysteine (NAC) orally. Subsequently, she developed fulminant hepatic failure with elevated transaminases, hypoglycemia, and coagulopathy (Tables 1A and 1B). She was transferred

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“…Hence, the generation of toxic reactive metabolites can occur in liver and extra‐hepatic tissues (Gu et al. 2005; Ding and Kaminsky 2003). Finally, besides mitochondrial dysfunction and oxidative stress, there is increasing evidence that ER stress can be another important mechanism in drug‐induced adverse effects, as underlined in this review.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

190

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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In Vivo Mechanisms of Tissue-Selective Drug Toxicity: Effects of Liver-Specific Knockout of the NADPH-Cytochrome P450 Reductase Gene on Acetaminophen Toxicity in Kidney, Lung, and Nasal Mucosa

Cited by 101 publications

References 30 publications

Acetaminophen Induced Kidney Failure in Rats: A Dose Response Study

Acetaminophen Induced Kidney Failure in Rats: A Dose Response Study

Acetaminophen-induced nephrotoxicity: Pathophysiology, clinical manifestations, and management

Role of endoplasmic reticulum stress in drug‐induced toxicity

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