Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity

Acuña, Gonzalo; Foernzler, Dorothee; Leong, Diane U.; Rabbia, Michael; Smit, R.; Dorflinger, Ernest; Gasser, Rodolfo; Hoh, Josephine; Ott, Jürg; Borroni, Edilio; To, Zung; Thompson, Annick; Li, Jia; Hashimoto, L.; Lindpaintner, Klaus

doi:10.1038/sj.tpj.6500123

Cited by 73 publications

(28 citation statements)

References 11 publications

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“…Some may have had genetic polymorphisms making them more susceptible to acetaminophen poisoning at lower doses, but most had ingested doses that would be expected to cause severe liver injury. 30,31 A second potential reason for toxicity is the simultaneous use of 2 preparations, recorded in 22% overall, and 38% of the unintentional group. Information was not available regarding the reason for the use of 2 preparations, but frustration, impulsivity, or simply lack of recognition of the presence of acetaminophen in both preparations have all been recognized.…”

Section: Discussionmentioning

confidence: 99%

Acetaminophen‐induced acute liver failure

et al. 2005

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Severe acetaminophen hepatotoxicity frequently leads to acute liver failure (ALF). We determined the incidence, risk factors, and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in the United States. Detailed prospective data were gathered on 662 consecutive patients over a 6-year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury. The annual percentage of acetaminophen-related ALF rose during the study from 28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent to 48 extra-strength tablets). Unintentional overdoses accounted for 131 (48%) cases, intentional (suicide attempts) 122 (44%), and 22 (8%) were of unknown intent. In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds. Eighty-one percent of unintentional patients reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%) died without transplantation, and 23 subjects (8%) underwent liver transplantation; 71% were alive at 3 weeks. Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups. In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and/or take several preparations simultaneously. Education of patients, physicians, and pharmacies to limit high-risk use settings is recommended. (HEPATOLOGY 2005;42:1364-1372

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Section: Discussionmentioning

confidence: 99%

Acetaminophen‐induced acute liver failure

et al. 2005

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“…It is also likely that other factors will contribute to the development of tolcapone hepatotoxicity. Indeed, a recent pharmacogenetic study showed that UDP-glucuronosyl transferase, an enzyme involved in the elimination of tolcapone, is associated with tolcapone-induced liver enzyme elevations (44). Thus, genes other than COMT should also be considered for personalized medicine using tolcapone.…”

Section: Orientation Of Catalytic Domain Of Mb-comt Is Critical For Dmentioning

confidence: 99%

Orientation and Cellular Distribution of Membrane-bound Catechol-O-methyltransferase in Cortical Neurons

Chen

Song

Yuan

et al. 2011

Journal of Biological Chemistry

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Background: COMT is a key enzyme for inactivation and metabolism of catechols, including dopamine. Results: MB-COMT is located in the cell body, axons and dendrites of cortical neurons, and oriented with its C-terminal catalytic domain in the extracellular space. Conclusion: MB-COMT can inactivate synaptic and extrasynaptic dopamine on surface of cortical neurons. Significance: MB-COMT specific inhibitors can be developed and may be less cytotoxic.

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“…(6)). For example, a recent retrospective study with 135 patients who had developed increased serum activities of ALT after administration of tolcapone revealed that these patients exhibited a significantly higher increase in single nucleotide polymorphisms (SNPs) in the UGT1A gene complex (UGT is involved in tolcapone elimination) [111]. 6.…”

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confidence: 99%

Bioactivation and Hepatotoxicity of Nitroaromatic Drugs

Boelsterli¹,

Ho²,

Zhou³

et al. 2006

CDM

165

116

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Certain drugs containing a nitroaromatic moiety (e.g., tolcapone, nimesulide, nilutamide, flutamide, nitrofurantoin) have been associated with organ-selective toxicity including rare cases of idiosyncratic liver injury. What they have in common is the potential for multistep nitroreductive bioactivation (6-electron transfer) that produces the potentially hazardous nitroanion radical, nitroso intermediate, and N-hydroxy derivative. These intermediates have been associated with increased oxidant stress and targeting of nucleophilic residues on proteins and nucleic acids. However, other mechanisms including the formation of oxidative metabolites and mitochondrial liability, as well as inherent toxicokinetic properties, also determine the drugs' overall potency. Therefore, structural modification not only of the nitro moiety but also of ring substituents can greatly reduce toxicity. Novel concepts have revealed that, besides the classical microsomal nitroreductases, cytosolic and mitochondrial enzymes including nitric oxide synthase can also bioactivate certain nitroarenes (nilutamide). Furthermore, animal models of silent mitochondrial dysfunction have demonstrated that a mitochondrial oxidant stress posed by certain nitroaromatic drugs (nimesulide) can produce significant mitochondrial injury if superimposed on a genetic mitochondrial abnormality. Finally, there may be mechanisms for all nitroaromatic drugs that do not involve bioactivation of the nitro group, e.g., AHR interactions with flutamide. Taken together, the focus of research on the hepatic toxicity of nitroarene-containing drugs has shifted over the past years from the identification of the reactive intermediates generated during the bioreductive pathway to the underlying biomechanisms of liver injury. Most likely one of the next paradigm shifts will include the identification of determinants of susceptibility to nitroaromatic drug-induced hepatotoxicity.

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Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity

Cited by 73 publications

References 11 publications

Acetaminophen‐induced acute liver failure

Acetaminophen‐induced acute liver failure

Orientation and Cellular Distribution of Membrane-bound Catechol-O-methyltransferase in Cortical Neurons

Bioactivation and Hepatotoxicity of Nitroaromatic Drugs

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