Opinion
Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis?

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The serologic hallmark of primary biliary cirrhosis (PBC) is the presence of antimitochondrial autoantibodies (AMAs) directed against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). The PBC-related autoepitope of PDC-E2 contains lipoic acid, and previous work has demonstrated that mimics of lipoic acid following immunization of mice lead to a PBC-like disease. Furthermore, approximately one-third of patients who have ingested excessive amounts of acetaminophen (paracetamol) develop AMA of the same specificity as patients with PBC. Quantitative structure–activity relationship (QSAR) data indicates that acetaminophen metabolites are particularly immunoreactive with AMA, and we submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate a loss of tolerance and lead to the development of PBC.

Section snippets

The natural history and genetics of primary biliary cirrhosis (PBC)

PBC is a middle-age onset, liver-specific autoimmune disease that has an average incidence of 2.7 cases per 100 000 in a well-defined US population [1], but epidemiological studies suggest that the incidence of PBC is increasing [2]. There is variation in the rates of disease between geographic locations 2, 3, and PBC is more prevalent in Northern Europe and North America and less common in Eastern Asia, Africa, and Australia 4, 5. It predominantly affects women with a female/male patient ratio

Immunological features

AMAs are present in over 95% of patients with PBC and are the most specific diagnostic antibody marker of PBC 24, 25. The autoantigens of AMAs have been identified as the E2 subunits of the 2-oxo-acid dehydrogenase complexes (2OADC-E2), including the E2 subunits of the pyruvate dehydrogenase complex (PDC-E2), branched chain 2-oxo acid dehydrogenase complex (BCOADC-E2), and 2-oxo-glutarate dehydrogenase complex (OGDC-E2) 26, 27, 28, 29, 30. The AMA target antigens are all localized to the inner

Susceptibility of the lipoyl domain to chemical modification

The uniqueness of AMA epitope specificity to the lipoyl domains of the 2OADC-E2 enzymes in patients with PBC suggests that the lipoic acid domain is likely to be a lynchpin to the etiology of PBC. In particular, the immune reactivity of AMAs is directed against a conformational epitope that includes a highly conserved lysine-lipoyl conjugate and the signature amino acid motifs Glu-Thr-Asp-Lys-Ala, Glu-Thr-Asp-Lys-(Thr), and (Gln-Ser)-Asp-Lys-Ala in PDC-E2, OGDC-E2, and BCOADC-E2, respectively 27

AMAs are present in sera of patients with acetaminophen-induced liver injuries

In the United States, most liver injury is the consequence of drug overdose. The liver is at risk for drug-induced injury because many environmental chemicals are metabolized primarily by hepatocytes [49]. The pathogenesis of most drug-induced liver injuries is initiated by the metabolic conversion of xenobiotics into reactive intermediate species, such as electrophilic compounds or free radicals, that can potentially alter the structure and function of cellular macromolecules to form

Mechanism of APAP metabolism and protein modification

APAP is the most widely used nonprescription drug in the United States, and at the recommended therapeutic dosage of 1000 mg per single dose (and up to 4000 mg per day for adults) 85% of ingested APAP is metabolized in the liver to nontoxic compounds via conjugation of the aromatic ring to sulfate or glucuronic acid. The remaining 15% is converted into a highly electrophilic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), by isozymes of microsomal cytochrome P450 [60]. In the presence of the

Significance of AMAs in the pathophysiology of BECs in PBC

Despite the fact that mitochondrial targets are proteins ubiquitously expressed in all nucleated cells, the immunopathology of PBC is characterized by the presence of CD4+ and CD8+ T cell infiltrates in liver and the specific destruction of small biliary epithelial cells (BECs) [6]. This apparent paradox suggests there are unique immunopathological characteristics of BECs, the target tissue. Previous work suggested that AMAs preferentially recognize PDC-E2 with reduced sulfhydryl groups, and

Concluding remarks and future directions

The identification of AMA reactive compounds such as 6,8-bis(acetylthio)octanoic acid, 8-(acetylthio)octanoic acid, and 6,8-bis(propionylthio)octanoic acid, which structurally resemble lipoic acid with a disrupted disulfide bond, and the presence of AMAs in acetaminophen overdose patients argue strongly that electrophilic drugs could modify the lipoic acid domain of PDC-E2 and break tolerance in genetically susceptible hosts. We are cognizant that the breaking of tolerance is crucial in the

Acknowledgments

This work is supported in part by National Institutes of Health grants DK39588 and DK067003. The authors would like to thank Mr Thomas Kenny and Ms Nikki Phipps for assistance in preparation of the manuscript.

Glossary

Ascites
accumulation of fluid in the peritoneal cavity, commonly due to cirrhosis and severe liver disease.
Bleeding varices
engorged veins are called varices; they are fragile and can bleed easily because veins are not designed to handle high internal pressures.
Cholangiocytes
epithelial cells of the bile duct.
Epitope spreading
the shifting of an immune reaction from its primary antigenic binding site to other targets. The new targets need not be structurally similar to the primary target.

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