Nitrofurantoin-Induced Hepatotoxicity Mediated by CD8+ T Cells

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.

show abstract

“…(5)). There is also a reported case of putative immune-mediated liver injury, which is most likely caused by a reactive metabolite [90].…”

Section: Nitrofurantoinmentioning

confidence: 97%

Bioactivation and Hepatotoxicity of Nitroaromatic Drugs

Boelsterli¹,

Ho²,

Zhou³

et al. 2006

CDM

165

116

View full text Add to dashboard Cite

show abstract

“…The time to recovery varied from 3 weeks to 6 months. Recovery of liver function was faster than or equal to that of pulmonary function in a few cases, 16,19,20,24 but not in others. 17,22 Two of the patients died of subsequent complications, despite corticosteroid therapy in one case.…”

Section: Discussionmentioning

confidence: 78%

“…Only articles published in English and searchable before October 2010 were included. The titles and abstracts were screened for relevance, and 9 published articles [16][17][18][19][20][21][22][23][24] describing 10 case reports were identified (Table 1). To the best of our knowledge, this is the first summary incorporating all cases of nitrofurantoin-induced concurrent pulmonary and hepatic toxicity published in English.…”

Section: Discussionmentioning

confidence: 99%

Nitrofurantoin-Associated Lung and Liver Toxicity Leading to Liver Transplantation in a Middle-Aged Patient

Kiang

Ford

Yoshida

et al. 2011

CJHP

View full text Add to dashboard Cite

“…Cytotoxic T-cells play a pivotal role in the pathogenesis of nitrofurantoininduced liver injury. It has been hypothesized that a breakdown product of the drug or the drug itself, bound to an endogenous peptide, is presented by the class 1 HLA antigen on the hepatocyte cell membrane; this induces cytotoxic Tcell activation and subsequent hepatocyte death 16 . Ethnicity or genetic background may be a risk factor because of the variability in detoxification mechanisms (acetylator phenotype, human leukocyte antigen group) 17 .…”

Section: Discussionmentioning

confidence: 99%