Autoantibodies against CYP2D6 and other drug-metabolizing enzymes in autoimmune hepatitis type 2

Autor:	Masakazu Shinoda, Takaharu Mizutani, Asuka Hattori, Takashi Osaka, Takuya Kuno, Yuta Tanaka, Nayumi Kuno, Toru Usui
Rok vydání:	2005
Předmět:	medicine.medical_specialty Autoimmune hepatitis medicine.disease_cause Epitope Autoimmunity Antigen Cytochrome P-450 Enzyme System Internal medicine medicine Animals Humans Pharmacology (medical) General Pharmacology Toxicology and Pharmaceutics Autoantibodies Autoimmune disease Hepatitis biology Autoantibody Cytochrome P450 medicine.disease Hepatitis Autoimmune Endocrinology Cytochrome P-450 CYP2D6 Immunology Inactivation Metabolic biology.protein
Zdroj:	Drug metabolism reviews. 37(1)
ISSN:	0360-2532
Popis:	Autoimmune hepatitis (AIH) is a disease of unknown etiology, characterized by liver-related autoantibodies. Autoimmune hepatitis is subdivided into two major types: AIH type 1 is characterized by the detection of ANA, SMA, ANCA, anti-ASGP-R, and anti-SLA/LP. Autoimmune hepatitis type 2 is characterized to be mainly related with drug-metabolizing enzymes as autoantigens, such as anti-LKM (liver-kidney microsomal antigen)-1 against CYP2D6, anti-LKM-2 against CYP2C9-tienilic acid, anti-LKM-3 against UGT1A, and anti-LC1 (liver cytosol antigen)-1 and anti-APS (autoimmune polyglandular syndrome type-1) against CYP1A2, CYP2A6, and others. Anti-LKM-1 sera inhibited CYP2D6 activity in vitro but did not inhibit cellular drug metabolism in vivo. CYP2D6 is the major target autoantigen of LKM-1 and expressed on plasma membrane (PM) of hepatocytes, suggesting a pathogenic role for anti-LKM-1 in liver injury as a trigger. Anti-CYP1A2 was observed in dihydralazine-induced hepatitis, and radiolabeled CYP1A2 disappeared from the PM with a half-life of less than 30 min, whereas microsomal CYP1A2 was stably radiolabeled for several hours. Main antigenic epitopes on CYP2D6 are aa 193-212, aa 257-269, and aa 321-351; and D263 is essential. The third epitope is located on the surface of the protein CYP2D6 and displays a hydrophobic patch that is situated between an aromatic residue (W316) and histidine (H326). Some drugs such as anticonvulsants (phenobarbital, phenytoin, and carbamazepine) and halothane are suggested to induce hepatitis with anti-CYP3A and anti-CYP2E1, respectively. Autoantibodies against CYP11A1, CYP17, and/or CYP21 involved in the synthesis of steroid hormones are also detected in patients with adrenal failure, gonadal failure, and/or Addison disease.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f071a3ee79046d89fe78866087e9b412 https://pubmed.ncbi.nlm.nih.gov/15747502 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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