Acetaminophen metabolic activation

Hinson, J.A. Reid, A.B. McCullough, S.S. James, L.P. (2004). Acetaminophen-induced hepatotoxicity role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metabolism Reviews, Vol.36, No. 3-4, (January 2004), pp. 805-822, ISSN 0360-2532. 

As previously mentioned, many of the enzymes involved in xenobiotic metabolism are inducible. Inducibility allows for more enzymatic activity, thereby ensuring an adequate detoxication response however, it also provides a mechanism whereby an activation pathway may be increased. This occurs in the example given earlier of the combined effects of ethanol and acetaminophen. When CYP2E1 is induced by ethanol prior to administration of acetaminophen, subsequent activation of acetaminophen to NAPQI is prevalent however, without induction by ethanol, CYP2E1 is not the predominant enzyme for metabolizing acetaminophen, and detoxication is favored. Interestingly, simultaneous administration decreases the toxicity of acetaminophen because both are substrates for 2E1 ethanol acts as a competitive inhibitor, thereby blocking the activation of acetaminophen. 

Much is known about the biochemical toxicology of hepatotoxicants, yet much remains to be learned. Hepatotoxicity resulting in either cell necrosis, fibrosis, or fatty infiltration is known to be a widespread phenomenon, potentially of importance to human health. It is caused by numerous drugs and environmental agents, and its incidence is expected to increase as confounding viral liver disease becomes more prevalent. Much is known about mechanisms based upon comprehensive studies with a few prototypical chemicals—namely, CCb, ethanol and acetaminophen—which support a convergence of varied primary effects on the ultimate failure of mitochondrial function and Ca2+ homeostasis. The extensive metabolic activity of the liver exposes its cells to a continuous flux of prooxidants. The importance of metabolic activation for the production of reactive metabolites is well-... 

The most commonly described mechanism proposes that metabolic activation occurs through V-oxidation of acetaminophen to V-hydroxyacetaminophen followed by dehydration to NAPQl (Figure 33.22). ... 

CAR in hepatocytes. However, PRIP is not required for nuclear translocation of CAR. Activation of CAR is known to increase acetaminophen hepatotoxicity by inducing acetaminophen-metabolizing enzymes in the liver [43]. Deficiency of PBP, but not of PRIP, abrogates acetaminophen hepatotoxicity [41],... 

Fig. 7 Metabolic activation of acetaminophen (APAP) and amodiaquine (AQ) to their respective quinoneimines. The stmctures of chloroquine and isoquine demonstrate their relative lack of chemical reactivity...

Davis DC, Potter WZ, follow DJ et al (1974) Species differences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen. Life Sci 14 2099-2109 Davis W, Venitt S, Phillips DH (1998) The metabolic activation of tamoxifen and a-hydroxyta-moxifen to DNA-binding species in rat hepatocytes proceeds via sulphation. Carcinogenesis 19 861-866... 

In general, phase I reactions, such as oxidation and ra-demethylation are delayed in the neonate but are fully operational at or above adult levels by 4-6 months of age in the full-term neonate [27a-30]. Conjugation pathways, such as glucuronidation, do not approach adult values until 3 or 4 years of age. Sulfation activity does appear to reach adult levels in early infancy. For drugs that are subject to metabolism by both pathways, such as acetaminophen, the efficient activity of the sulfation pathway allows infants and children to compensate for low glucuronidation ability... 

Sulfotransferases (SULTs) are important for the metabolism of a number of drugs, neurotransmitters, and hormones, especially the steroid hormones. The cosubstrate for these reactions is 3 -phosphoadenosine 5 -phosphosulfate (PAPS) (Fig. 4.1). Like the aforementioned enzymes, sulfate conjugation typically renders the compound inactive and more water soluble. However, this process can also result in the activation of certain compounds, such as the antihypertensive minoxidil and several of the steroid hormones. Seven SULT isoforms identified in humans, including SULTs lAl to 1A3, possess activity toward phenolic substrates such as dopamine, estradiol, and acetaminophen. SULTIBI possesses activity toward such endogenous substrates as dopamine and triiodothyronine. SULTIEI has substantial activity toward steroid hormones, especially estradiol and dehydroepiandrosterone, and toward the anti-... 

Pharmacokinetics Rapidly, completely absorbed from G1 tract rectal absorption variable. Widely distributed to most body tissues. Acetaminophen is metabolized in liver excreted in urine. Dichloralphenazone is hydrolyzed to active compounds chloral hydrate and antipyrine. Chloral hydrate is metabolized in the liver and erythrocytes to the active metabolite trichloroethanol, which maybe further metabolized to inactive metabolite. It is also metabolized in the liver and kidneys to inactive metabolites. The pharmacokinetics of isometheptene is not reported. Removed by hemodialysis. Half-life Acetaminophen 1-4 hr (half-life is increased in those with liver disease, elderly, neonates decreased in children). 

Acetaminophen is one of the most important drugs used in the treatment of mild to moderate pain when an anti-inflammatory effect is not necessary. Phenacetin, a prodrug that is metabolized to acetaminophen, is more toxic than its active metabolite and has no rational indications. 

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