A 42-year-old man is brought to the emergency department after a suspected suicide attempt. The patient's wife filed for divorce a few days ago, and 3 hours ago, he began drinking alcohol and took multiple acetaminophen tablets. He has had several episodes of vomiting. The patient has no significant history of alcohol use, and he last drank alcohol 6 months ago. Vital signs are stable. Laboratory results are pending. The patient's family is concerned about significant liver injury given his concurrent alcohol and acetaminophen intake. A physician explains to the family that acute ethanol ingestion may reduce the risk of acetaminophen-induced liver toxicity. Which of the following actions of ethanol best explains this phenomenon?

Question

A 42-year-old man is brought to the emergency department after a suspected suicide attempt.  The patient's wife filed for divorce a few days ago, and 3 hours ago, he began drinking alcohol and took multiple acetaminophen tablets.  He has had several episodes of vomiting.  The patient has no significant history of alcohol use, and he last drank alcohol 6 months ago.  Vital signs are stable.  Laboratory results are pending.  The patient's family is concerned about significant liver injury given his concurrent alcohol and acetaminophen intake.  A physician explains to the family that acute ethanol ingestion may reduce the risk of acetaminophen-induced liver toxicity.  Which of the following actions of ethanol best explains this phenomenon?

Quizplus · Accepted Answer

11ec160b_3bc7_be79_9249_fb62374b1475_MD0001_00 Acetaminophen is a commonly used antipyretic and analgesic drug that is metabolized by the liver. Although it is mostly converted to nontoxic metabolites by sulfation and glucuronidation, a small amount of the drug is metabolized by cytochrome P450 enzymes (including subtype 2E1) into the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). When acetaminophen dosage is appropriate, NAPQI is conjugated by glutathione into a nontoxic compound and eliminated in the urine. However, an acetaminophen overdose depletes intrahepatic glutathione, causing the NAPQI level to rise and cause hepatotoxicity. Concomitant acute ethanol ingestion can potentially reduce acetaminophen-induced hepatotoxicity. Although ethanol is primarily metabolized by alcohol dehydrogenase, it can also be converted to acetaldehyde by cytochrome P450 2E1. Through competitive inhibition of cytochrome P450 2E1, ethanol can decrease metabolism of acetaminophen to NAPQI and therefore decrease NAPQI concentrations. Notably, although some of these patients may experience less hepatotoxicity from acetaminophen overdose than expected, the amount of ethanol that confers this protective effect is unknown and ethanol should therefore not be considered an antidote for acetaminophen toxicity. Moreover, ethanol itself can cause hepatotoxicity when consumed excessively. (Choices B and E) In contrast to acute ethanol ingestion, chronic consumption can lead to nutritional deficiencies and chronic oxidative damage that decrease intrahepatic glutathione synthesis. In addition, cytochrome P450 2E1 activity is upregulated by chronic ethanol use. As a result chronic alcohol consumption increases NAPQI concentrations and the risk of hepatotoxicity during an acetaminophen overdose. (Choice C) Impairment of glucuronidation would decrease conversion of acetaminophen to nontoxic metabolites and increase the amount of acetaminophen converted to NAPQI, worsening hepatotoxicity. (Choice D) Activated charcoal is a highly absorbent powder that binds to drugs and toxins, including acetaminophen, and is sometimes used to limit intestinal absorption after an overdose. However, ethanol does not affect intestinal absorption of acetaminophen. Educational objective: Acetaminophen and ethanol are metabolized by same cytochrome P450 enzyme. Through competitive inhibition, acute (not chronic) ingestion of ethanol can lead to decreased conversion of acetaminophen to N-acetyl-p-benzoquinone imine (a toxic metabolite), potentially reducing acetaminophen-induced hepatotoxicity. However, cytochrome P450 2E1 activity is upregulated by chronic ethanol use. As a result chronic alcohol consumption increases NAPQI concentrations and the risk of hepatotoxicity during an acetaminophen overdose. __________ References: Acute ethanol coingestion confers a lower risk of hepatotoxicity after deliberate acetaminophen overdose. (http://www.ncbi.nlm.nih.gov/pubmed/18211314)

A 42-Year-Old Man Is Brought to the Emergency Department After