Role of the human N-acetyltransferase 2 genetic polymorphism in metabolism and genotoxicity of 4, 4′-methylenedianiline

Salazar‐González, Raúl A.; Zhang, Xiaoyan; Doll, Mark A.; Lykoudi, Angeliki; Hein, David W.

doi:10.1007/s00204-019-02516-4

Cited by 7 publications

(2 citation statements)

References 47 publications

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“…Remarkably, several products with significant exposure potential to newborns contained Diphenylmethane diisocyanate (MDI), the most common and extensively used diisocyanate intermediate of the polyurethane chemical (PUC) industry ( 67 ). MDI is derived from another commonly used PUC, 4, 4’-Methylenedianiline (MDA), a hepatotoxin known to induce liver injury in multiple rodent studies and responsible for an outbreak of jaundice in the Epping district of Essex (“Epping jaundice”) in early 1965 which affected 84 people ( 68 ). In rodents, administration of MDA causes hepatic necroinflammation and fibrosis and portal inflammation, eosinophilic infiltration, cholangitis, cholestasis, and varying degrees of hepatocellular damage in humans.…”

Section: Triggers Of Ba: Advances and Mechanismsmentioning

confidence: 99%

Recent developments in etiology and disease modeling of biliary atresia: a narrative review

et al. 2020

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Biliary atresia (BA) is a rare but severe fibroinflammatory disease of the extrahepatic and the intrahepatic bile ducts. Without prompt interventions, BA has fatal outcomes and is the most common indicator for pediatric liver transplantation (LTx). While the mainstay of treatment involves surgically correcting the extrahepatic biliary obstruction via Kasai hepato-portoenterostomy (KHPE), activation of a multitude of biological pathways and yet-to-be-determined etiology in BA continue to foster liver inflammation, cirrhosis and need for LTx. However, important caveats still exist in our understandings of the biliary pathophysiology, the rapidity of liver fibrosis and progression to liver failure, largely due to limited knowledge of the triggers of biliary injury and the inability to accurately model human BA. Although inconclusive, a large body of existing literature points to a potential viral infection in the early peri- or postnatal period as triggers of epithelial injury that perpetuates the downstream biliary disease. Further confounding this issue, are the lack of in-vivo and in-vitro models to efficiently recapitulate the cardinal features of BA, primarily liver fibrosis. To overcome these barriers in BA research, new directions in recent years have enabled (I) identification of additional triggers of biliary injury linked mostly to environmental toxins, (II) development of models to investigate liver fibrogenesis, and (III) translational research using patient-derived organoids. Here, we discuss recent advances that undoubtedly will stimulate future efforts investigating these new and exciting avenues towards mechanistic and drug discovery efforts and disease-preventive measures. The implications of these emerging scientific investigations and disease modeling in severe fibrosing cholangiopathies like BA are enormous and contribute substantially in our understandings of this rare but deadly disease. These findings are also expected to facilitate expeditious identification of translationally targetable pathways and bring us one step closer in treating an infant with BA, a population highly vulnerable to life-long liver related complications.

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Section: Triggers Of Ba: Advances and Mechanismsmentioning

confidence: 99%

Recent developments in etiology and disease modeling of biliary atresia: a narrative review

et al. 2020

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“…Our samples were also analysed for MDI-lysine (without acetylation) but the levels were very low (data not shown), indicating that this was not a significant biomarker, at least in these particular samples. The variability in human acetylator phenotypes (Kadlubar et al, 1992; Salazar-González et al, 2019) will impact the extent of formation of acMDI-Lys in individual workers. It is also possible that different routes of exposure (skin uptake versus inhalation) may impact the metabolite profile.…”

Section: Resultsmentioning

confidence: 99%

Methylenediphenyl diisocyanate lysine conjugates in the urine of workers exposed to methylenediphenyl diisocyanate

2022

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Diisocyanates have long been a leading cause of occupational asthma. As control often relies on personal protective equipment and there is the potential for skin uptake, biological monitoring is often used to assess worker exposure. Current routine biological monitoring methods do not distinguish between a diisocyanate and the corresponding diamine exposure in urine samples; therefore, a specific urinary biomarker is desirable. Urine samples were obtained from a group of workers exposed to methylenediphenyl diisocyanate (MDI) where aerosol generation was unlikely. Lysine conjugates of MDI were extracted from urine by solid phase extraction; analysis was performed by liquid chromatography tandem mass spectrometry. Acetylated MDI-lysine (acMDI-Lys) conjugates were detected in 73% of samples tested from persons with exposure to MDI compared to 93% of samples that were positive for methylene dianiline (MDA) in hydrolysed urine. There was a weak but significant positive correlation between the two biomarkers (r2 = 0.377). This is the first report detecting and quantifying acMDI-Lys in the urine of workers exposed to MDI, and acMDI-Lys may be a useful non-invasive biomarker in discriminating between MDI and MDA exposures.

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Identification and characterization of potent, selective, and efficacious inhibitors of human arylamine N-acetyltransferase 1

et al. 2021

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Role of the human N-acetyltransferase 2 genetic polymorphism in metabolism and genotoxicity of 4, 4′-methylenedianiline

Cited by 7 publications

References 47 publications

Recent developments in etiology and disease modeling of biliary atresia: a narrative review

Recent developments in etiology and disease modeling of biliary atresia: a narrative review

Methylenediphenyl diisocyanate lysine conjugates in the urine of workers exposed to methylenediphenyl diisocyanate

Identification and characterization of potent, selective, and efficacious inhibitors of human arylamine N-acetyltransferase 1

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