Interindividual variability in P450-dependent generation of neoantigens in halothane hepatitis

Eliasson, Erik; Gardner, Iain; Hume-Smith, Helen; Waziers, Isabelle de; Beaune, Philippe; Kenna, J. Gerry

doi:10.1016/s0009-2797(98)00081-7

Cited by 39 publications

(17 citation statements)

References 45 publications

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“…Assay of N,N-Dimethylnitrosamine N-Demethylation Activity-N-Demethylation of N,N-dimethylnitrosamine was assayed according to Eliasson et al (61,62) in the presence of added 0.2 nmol of Adx, 0.02 nmol of Adr, and 300 g of mitochondrial protein/ml as enzyme source. In assays with the microsomal fractions, the microsome-associated NPR served as an electron donor for the reaction.…”

Section: Methodsmentioning

confidence: 99%

Human Cytochrome P450 2E1 Mutations That Alter Mitochondrial Targeting Efficiency and Susceptibility to Ethanol-induced Toxicity in Cellular Models

Bansal

Anandatheerthavarada

Prabu

et al. 2013

Journal of Biological Chemistry

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Background: Induced expression of CYP2E1 is known to enhance alcohol liver toxicity. Results: Novel mutations W23R/W30R and L32N in human CYP2E1 alter mitochondrial and microsomal targeting efficiency. Conclusion: Human variants with altered targeting modulate susceptibility of cells to alcohol. Significance: Carriers of the novel W23R/W30R mutation in CYP2E1 are likely to be more susceptible to alcohol toxicity.

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Section: Methodsmentioning

confidence: 99%

Human Cytochrome P450 2E1 Mutations That Alter Mitochondrial Targeting Efficiency and Susceptibility to Ethanol-induced Toxicity in Cellular Models

Bansal

Anandatheerthavarada

Prabu

et al. 2013

Journal of Biological Chemistry

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“…One of several examples hereof is halothane hepatitis. The major enzyme responsible for halothane bioactivation to trifluoroacetylchloride is cytochrome P450 2E1 (CYP2E1), which in turn becomes alkylated and thereby immunogenic (Eliasson and Kenna, 1996;Eliasson et al, 1998). Around 70% of patients with halothane hepatitis express high titers of anti-CYP2E1-autoantibodies as well as antibodies to a number of trifluoroacetylated microsomal proteins (Kenna et al, 1987;Eliasson and Kenna, 1996).…”

Section: Reactive Intermediates and Autoimmunitymentioning

confidence: 99%

“…Around 70% of patients with halothane hepatitis express high titers of anti-CYP2E1-autoantibodies as well as antibodies to a number of trifluoroacetylated microsomal proteins (Kenna et al, 1987;Eliasson and Kenna, 1996). Reduced GSH protects endoplasmic reticulum proteins from trifluoroacetylation (Eliasson et al, 1998), but whether this is catalyzed by MGST1 is not known. We have investigated whether there is an anti-MGST1 immune response in halothane hepatitis.…”

Section: Reactive Intermediates and Autoimmunitymentioning

confidence: 99%

Reactive Intermediates and The Dynamics of Glutathione Transferases

Rinaldi

Eliasson²,

Swedmark³

et al. 2002

Drug Metab Dispos

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123

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ABSTRACT:Reactive intermediates are a continuous burden in biology and several defense mechanisms have evolved. Here we focus on the functions of glutathione transferases (GSTs) with the aim to discuss the quantitative aspects of defense against reactive intermediates. Humans excrete approximately 0.1 mmol of thioether conjugates per day. As the amount of GST active sites in liver is Ϸ0.5 mmol, it appears that glutathione transferase catalysts are present in tremendous excess. In fact, the known catalytic properties of GSTs reveal that the enzymes can empty the liver glutathione (GSH) pool in a matter of seconds when provided with a suitable substrate. However, based on the urinary output of conjugates (or derivatives thereof), individual GSTs turn over (i.e., catalyze a single reaction) only once every few days. Glutathione transferase overcapacity reflects the fact that there is a linear relation between GST enzyme amount and protection level (provided that GSH is not depleted). Put in a different perspective, a few reactive molecules will always escape conjugation and reach cellular targets. It is therefore not surprising that signaling systems sensing reactive intermediates have evolved resulting in the increase of GSH and GST levels. Precisely for this reason, more moderately reactive electrophiles (Michael acceptors) are receiving growing interest due to their anticarcinogenic properties. Another putative regulatory mechanism involves direct activation of microsomal GST1 by thiol-reactive electrophiles through cysteine 49. The toxicological significance of low levels of reactive intermediates are of interest also in drug development, and here we discuss the use of microsomal GST1 activation as a surrogate detection marker.

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“…40 The most intimately associated xenobiotic-induced liver disease associated with PBC, halothane hepatitis, occurs when susceptible patients mount an immune response to trifluoroacetylated protein antigens, formed following cytochrome P450 -mediated bioactivation of halothane to trifluoroacetyl chloride. 41 Exposure to trifluoroacetyl acid (TFA)-conjugated self proteins, both in humans and experimental animals, has led to antibody responses against such TFA-self proteins. Christen et al 42 have further shown that only the lipoylated form of the recombinant inner domain of the human PDC-E2, but not the unlipoylated form, was recognized by this antibody.…”

Section: Chemical Xenobiotic and Diseasementioning

confidence: 99%