PMID- 9328334
OWN - NLM
STAT- MEDLINE
DCOM- 19971023
LR  - 20161124
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 26
IP  - 4
DP  - 1997 Oct
TI  - Cytochromes P450 and uridine triphosphate-glucuronosyltransferases: model 
      autoantigens to study drug-induced, virus-induced, and autoimmune liver disease.
PG  - 1054-66
AB  - Enzymes of phase I (cytochromes P450) and phase II (UDP [uridine 
      diphosphate]-glucuronosyltransferases) of drug metabolism are targets of 
      autoimmunity in the following chronic liver diseases of different etiology: 
      1)autoimmune hepatitis (AIH); 2) hepatitis associated with the autoimmune 
      polyendocrine syndrome type 1 (APS-1); 3) virus-induced autoimmunity; and 4) 
      drug-induced hepatitis. AIH is diagnosed by the following: the absence of 
      infection with hepatitis viruses; the presence of a threshold of relevant 
      factors, including circulating autoantibodies, hypergammaglobulinemia, female sex 
      (female/male ratio 4:1), human leukocyte antigen (HLA) B8, DR3, or DR4; and 
      benefit from immunosuppression. Patients with autoimmune hepatitis type 2 (AIH-2) 
      are characterized by antibodies directed against liver and kidney microsomes, by 
      an early onset of autoimmune hepatitis, which is a more aggressive course of the 
      disease, and by a higher prevalence of autoimmunity directed against other 
      organs. The major target of autoimmunity in patients with AIH-2 is cytochrome 
      P450 2D6. Epitope mapping experiments revealed four short linear epitopes on 
      cytochrome P450 2D6, recognized by liver/kidney microsomal autoantibodies type 1 
      (LKM-1) in patients with AIH-2. In addition, about 10% of the patient sera 
      contain autoantibodies that detect a conformational epitope on 
      UDP-glucuronosyltransferases (UGTs) of family 1. Presently, LKM-1 autoantibodies 
      are used as diagnostic markers for AIH-2. It is unclear whether these 
      autoantibodies have a pathogenetic role. Hepatitis is found in some patients with 
      APS-1. Presumably this also is an autoimmune liver disease. APS-1 patients with 
      hepatitis may develop autoantibodies directed against microsomal P450 enzymes of 
      the liver; however, these autoantibodies do not recognize cytochrome P450 2D6, 
      but they do recognize cytochrome P450 1A2. Autoimmunity in patients with APS-1 
      usually is directed against several organs simultaneously, and several organ 
      specific autoantibodies may exist. Interestingly, APS-1 patients may produce 
      various anti-cytochrome P450 antibodies. In addition to the hepatic 
      anti-cytochrome P450, 1A2 autoantibodies are directed against steroidogenic 
      cytochromes P450, namely P450 c21, P450 scc, and P450 c17. These autoantibodies 
      correlate with adrenal and ovarian failure and often these steroidal cell 
      autoantibodies precede the manifestation of adrenal or ovarian dysfunction. 
      Whether anti-P450 1A2 autoantibodies have a similar predictive value is not yet 
      known. LKM autoantibodies are further found in association with chronic hepatitis 
      C and D. In chronic hepatitis C, the major target of LKM autoantibodies is 
      cytochrome P450 2D6. Predominantly, conformational epitopes are recognized by 
      LKM-1 sera of patients with chronic hepatitis C. In 13% of patients with chronic 
      hepatitis D, LKM-3 autoantibody is detectable. The target proteins are UGTs of 
      family 1 and in a minority of sera UGTs of family 2. The epitopes are 
      conformational. All hepatic diseases discussed earlier have in common that 
      autoimmunity, which is directed against enzymes of drug metabolizing multigene 
      families. Each disease is characterized by a specific pattern of autoantibodies, 
      with apparently little overlap. For example, LKM-1 autoantibodies, which are 
      directed against P450 2D6, seem to overlap between AIH and chronic hepatitis C. 
      However, a close examination of these autoantibodies shows differences between 
      LKM-1 autoantibodies from patients with chronic hepatitis C and with AIH. In AIH, 
      LKM autoantibodies are more homogenous, titers are higher, and major autoepitopes 
      on cytochrome P450 2D6 are small and linear. LKM autoantibodies in viral 
      hepatitis C are more heterogeneous and there are multiple epitopes, many of which 
      are conformational. These differences indicate the different mechanisms that are 
      involved in the generation of autoimmunity. (ABSTRACT TRUNCATED)
FAU - Manns, M P
AU  - Manns MP
AD  - Department of Gastroenterology and Hepatology, Hannover Medical School, Germany.
FAU - Obermayer-Straub, P
AU  - Obermayer-Straub P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Autoantigens)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Autoantigens/*immunology
MH  - Autoimmune Diseases/*etiology
MH  - Chemical and Drug Induced Liver Injury/immunology
MH  - Cytochrome P-450 Enzyme System/*immunology
MH  - Glucuronosyltransferase/*immunology
MH  - Hepatitis, Viral, Human/immunology
MH  - Humans
MH  - Liver Diseases/*etiology
MH  - Liver Regeneration
MH  - Molecular Sequence Data
RF  - 147
EDAT- 1997/10/27 00:00
MHDA- 1997/10/27 00:01
CRDT- 1997/10/27 00:00
PHST- 1997/10/27 00:00 [pubmed]
PHST- 1997/10/27 00:01 [medline]
PHST- 1997/10/27 00:00 [entrez]
AID - S027091399700459X [pii]
AID - 10.1002/hep.510260438 [doi]
PST - ppublish
SO  - Hepatology. 1997 Oct;26(4):1054-66. doi: 10.1002/hep.510260438.