Potentiation of Acetaminophen Hepatotoxicity by Alcohol

Abstract

Severe liver failure developed in three chronic alcoholics after they ingested acetaminophen for therapeutic reasons. The clinical course was characterized by SGOT levels of 5,000 to 10,000 IU. Concomitant renal failure developed in two of these patients, and one died in hepatic coma. To determine whether alcohol enhances acetaminophen hepatotoxicity, a lethal dose for 50% survival of a test group (LD50) was performed for mice fed 10% alcohol in their water supply for three weeks and for mice receiving a normal diet only. A significant reduction in the LD50 was seen in the alcohol-pretreated mice, and correlations were noted between histological findings in the liver and the LD50 data. These findings suggest that alcohol enhances acetaminophen hepatotoxicity in mice and provides supportive evidence that these three alcoholic patients probably had a similar pathophysiological basis for their liver disease.

Acetaminophen (APAP) hepatotoxicity—Isn’t it time for APAP to go away?

“…13-16 This has been underlined in recent studies showing high rates of polysubstance abuse, including cocaine and benzodiazepines, in addition to alcohol and opioids. 39 Again, there are similarities between intentional and unintentional groups as shown in a recent questionnaire study: the incidence of depressive disorder at any time, use of SSRI and SNRI medication, as well as use of alcohol were similar between the two groups, although opioid use was more prevalent in the unintentional group (Table 3).…”

“…Acetaminophen's popularity rose dramatically, despite the fact that virtually all Reyes cases were confined to children, not adults. 12 In the late 1970's and early 1980's, numerous reports surfaced regarding severe liver injury associated not with suicide attempts but as so-called ‘therapeutic misadventures.’ 13-15 These represented inadvertent overdoses in the setting of acute or chronic pain, often accompanied by alcohol use and without suicidal intent. Over the next decade, U.S. hepatologists became increasingly aware of this entity.…”

Metabolism and Disposition of Acetaminophen: Recent Advances in Relation to Hepatotoxicity and Diagnosis

“…Cysteine residues are the major targets for covalent modification by the reactive intermediate of APAP (70), though binding to lysine has also been reported and may contribute to mitochondrial damage during APAP toxicity (71) and it is possible that other amino acids react with NAPQI under certain conditions. The observation that alcohol and isoniazid could affect APAP-induced liver injury led to the hypothesis that CYP2E1 is the major P450 responsible for conversion of APAP to NAPQI (72–77). Accordingly, Cyp2e1 knockout mice were found to be less susceptible to APAP-induced liver injury (78).…”

“…There is also limited evidence for inhibition of metabolism and reduced toxicity as a result of alcohol co-ingestion in humans (110,151–152), although this is controversial (150,153). While acute ethanol exposure may reduce APAP-induced liver injury, chronic alcohol exposure can increase the metabolic activation and toxicity of APAP in rodents (72–73). The same effects may also occur in humans (77,153–154), though this too is controversial (155).…”

Hepatoprotective activity ofAmomum subulatumRoxb against ethanol-induced liver damage

“…[23] Acetaldehyde is thought to have a number of adverse effects like decreased transport and secretion of proteins due to tubulin polymerization, enhanced vitamin metabolism, and trace metals and drugs like paracetamol cause severe acute liver injury which is sometimes fatal. [24][25][26] Antioxidants exhibit hepatoprotective activity by blocking the conversion of ethanol to acetaldehyde. [27] Phytoconstituents like flavonoids, terpenoids, glycosides and volatile oils [28][29][30][31] are well known for their antioxidant and hepatoprotective activities.…”