Anti‐cytochrome P450 autoantibodies in drug‐induced disease

Beaune, Philippe; Lecoeur, Sylvaine; Gauffre, Aline; Dansette, Patrick M.; Mansuy, Daniel

doi:10.1111/j.1600-0609.1996.tb01652.x

Cited by 31 publications

(17 citation statements)

References 15 publications

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“…These results imply that dasatinib may potentially have pharmacokinetic drug-drug interactions when it is coadministered with drugs that are CYP3A4 substrates. In addition, in a small percentage of individuals, immunemediated idiosyncratic hepatotoxicity may be observed by dasatinib adducting to cellular proteins in a manner similar to that of diclofenac (Schapira et al, 1986), carbamazepine (Moore et al, 1985;Wu et al, 2006), tienilic acid (Homberg et al, 1984), or dihydralazine (Beaune et al, 1996;Masubuchi and Horie, 2007).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Dasatinib and Its Structural Analogs as CYP3A4 Mechanism-Based Inactivators and the Proposed Bioactivation Pathways

He²,

Ruiz³

et al. 2009

Drug Metab Dispos

113

105

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ABSTRACT:Dasatinib was approved in 2006 for the treatment of imatinibresistant chronic myelogenous leukemia and functions primarily through the inhibition of BCR-ABL and Src kinase. Dasatinib is extensively metabolized in humans by CYP3A4. In this study, we report that the bioactivation of dasatinib by CYP3A4 proceeds through a reactive intermediate that leads to CYP3A4 inactivation with K I ‫؍‬ 6.3 M and k inact ‫؍‬ 0.034 min ؊1. The major mechanism of inactivation proceeds through hydroxylation at the para-position of the 2-chloro-6-methylphenyl ring followed by further oxidation, forming a reactive quinone-imine, similar to the reactive intermediates formed by acetaminophen and diclofenac. Formation of a reactive imine-methide was also detected but appears to be a minor pathway. When glutathione was added to human liver microsomal incubations, dasatinib-glutathione adducts were detected. Numerous dasatinib analogs were synthesized in an effort to understand what modifications would block the formation of reactive intermediates during dasatinib metabolism. It is interesting to note that blocking the site of hydroxylation with a methyl group was not effective because a reactive imine-methide was formed, nor was blocking the site with fluorine because the fluorine was removed through an oxidative defluorination mechanism and the reactive quinone-imine was still formed. Numerous analogs are presented that did effectively block the formation of glutathione adducts and prevent the inactivation of CYP3A4.

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Section: Discussionmentioning

confidence: 99%

Characterization of Dasatinib and Its Structural Analogs as CYP3A4 Mechanism-Based Inactivators and the Proposed Bioactivation Pathways

He²,

Ruiz³

et al. 2009

Drug Metab Dispos

113

105

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“…Drugs with an aromatic functional group (furans and thiophenes) commonly form reactive metabolites [182,183], and the enzymes that generate these metabolites are frequently targeted by autoantibodies [184]. Phase I (CYP) drug-metabolizing enzymes are expressed on the hepatocyte surface, and distinctive antibodies to these CYP have characterized the prototypic forms of autoimmune-like hepatitis associated with tienilic acid, dihydralazine, and halothane [124,184].…”

Section: Pathogenic Mechanismsmentioning

confidence: 99%

“…Antinuclear antibodies and SMA are the most common serological markers of drug-induced autoimmune-like hepatitis [31], and their presence mimics the phenotype of classical type 1 autoimmune hepatitis [121]. Antibodies to liver kidney microsome type 2 (anti-LKM2) and antibodies to P4502C9 are expressed in the autoimmune-like hepatitis induced by tienilic acid [122][123][124][125]; antibodies to P4501A2 are expressed in the autoimmune-like hepatitis induced by dihydralazine [124,126,127]; and antibodies to tri-fluoroacetylated proteins that cross-react with the E2 subunit of pyruvate dehydrogenase are present in the autoimmunelike hepatitis induced by halothane [102]. Tienilic acid and dihydralazine have been withdrawn from the marketplace, and halothane is rarely used in the United States.…”

Section: Clinical Phenotype Of Drug-induced Autoimmune-like Hepatitismentioning

confidence: 99%

Drug-Induced Autoimmune-Like Hepatitis

2011

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The clinical phenotype of classical autoimmune hepatitis can be mimicked by idiosyncratic drug-induced liver injury, and differentiation can be difficult. The goals of this review are to enumerate the major agents of drug-induced autoimmune-like hepatitis, describe the clinical findings and risk factors associated with it, detail the clinical tools by which to assess causality, discuss putative pathogenic mechanisms, and describe treatment and outcome. The frequency of drug-induced autoimmune-like hepatitis among patients with classical features of autoimmune hepatitis is 9%. Minocycline and nitrofurantoin are implicated in 90% of cases. Female predominance, acute onset, and absence of cirrhosis at presentation are important clinical manifestations. Genetic factors affecting phase I and phase II transformations of the drug, polymorphisms that protect against cellular oxidative stress, and human leukocyte antigens that modulate the immune response may be important pathogenic components. Clinical judgment is the mainstay of diagnosis as structured diagnostic methods for drug-induced liver injury are imperfect. The covalent binding of a reactive drug metabolite to a hepatocyte surface protein (commonly a phase I or phase II enzyme), formation of a neoantigen, activation of CD8 T lymphocytes with nonselective antigen receptors, and deficient immune regulatory mechanisms are the main bases for a transient loss of self-tolerance. Discontinuation of the offending drug is the essential treatment. Spontaneous improvement usually ensues within 1 month. Corticosteroid therapy is warranted for symptomatic severe disease, and it is almost invariably effective. Relapse after corticosteroid withdrawal probably does not occur, and its absence distinguishes drug-induced disease from classical autoimmune hepatitis.

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“…Medications implicated in this form of liver injury are being cataloged, and minocycline and nitrofurantoin head the list [27,185,201]. Drug structures commonly converted to reactive metabolites that are associated with autoimmune manifestations (aromatic functional groups) have been recognized [205,209]; the phase I drug-metabolizing enzymes that commonly generate the reactive metabolites have been identified [200,204,210,211]; and the genetic factors affecting the phase I and phase II drug transformations are being described [192]. Recently, thymic stromal lymphopoietin (TSLP) has been recognized as a requisite for experimental, halothane-induced, immunemediated liver injury [212].…”

Section: Insights Into Drugs As Causes Of Autoimmune Hepatitismentioning

confidence: 99%

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis

Czaja

2015

Dig Dis Sci

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Autoimmune hepatitis lacks an identifiable cause, and its diagnosis requires the exclusion of etiologically defined diseases that resemble it. Insights into its pathogenesis are moving autoimmune hepatitis from an idiopathic to explainable disease, and the goal of this review is to describe the insights that are hastening this transition. Two types of autoimmune hepatitis are justified by serological markers, but they also have distinctive genetic associations (DRB1 and DQB1 genes) and autoantigens. DRB1 alleles are the principal susceptibility factors in white adults, and a six amino acid sequence encoded in the antigen-binding groove of class II molecules of the major histocompatibility complex can influence the selection of autoantigens. Polymorphisms, including variants of SH2B3 and CARD10 genes, may affect immune reactivity and disease severity. The cytochrome mono-oxygenase, CYP2D6, is the autoantigen associated with type 2 autoimmune hepatitis, and it shares homologies with multiple viruses that might promote self-intolerance by molecular mimicry. Chemokines, especially CXCL9 and CXCL10, orchestrate the migration of effector cells to sites of injury and are associated with disease severity. Cells of the innate and adaptive immune responses promote tissue damage, and possible deficiencies in the number and function of regulatory T cells may facilitate the injurious process. Receptor-mediated apoptosis is the principal mechanism of hepatocyte loss, and cell-mediated and antibody-dependent mechanisms of cytotoxicity also contribute. Insights that explain autoimmune hepatitis will allow triggering exogenous antigens to be characterized, risk management to be improved, prognostic indices to be refined, and site-specific therapeutic interventions to emerge.

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Anti‐cytochrome P450 autoantibodies in drug‐induced disease

Cited by 31 publications

References 15 publications

Characterization of Dasatinib and Its Structural Analogs as CYP3A4 Mechanism-Based Inactivators and the Proposed Bioactivation Pathways

Characterization of Dasatinib and Its Structural Analogs as CYP3A4 Mechanism-Based Inactivators and the Proposed Bioactivation Pathways

Drug-Induced Autoimmune-Like Hepatitis

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis

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