Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis

https://doi.org/10.1016/j.jaut.2006.06.002Get rights and content

Abstract

Antimitochondrial antibodies (AMA) are unique among autoimmune serologic reactants because of their extremely high association with the index disease primary biliary cirrhosis (PBC). This autoantibody response is specifically directed only to the lipoyl domain of the mitochondrial 2-oxo-acid dehydrogenase complexes, which prompted us to search for environmental mimotopes in the form of xenobiotics and led to our identification of 2-octynoic acid as a high-affinity reactant for AMA. To focus on the chemical characteristics requisite for binding of AMA to the xenobiotic-modified self-peptide, quantitative structure–activity relationship (QSAR) studies were performed using a panel of alkynoic compounds, including examination of the length of the carbon chain and the location of the triple bond in the identified mimotope. Analyses of octynamides that varied in the position of the triple bond demonstrated that only the 2-octynamide reacted strongly with PBC sera. Furthermore, among 2-alkynamides with varying carbon chain length, 2-octyn-, 2-nonyn- (particularly) and 2-decynamide exhibited the highest reactivity. Thus, an optimal chemical structure of the xenobiotically modified epitope recognized by AMA-positive PBC sera is provided by 2-nonynoic acid. The methyl ester of this compound is ranked 2324th out of 12,945 compounds to which there is occupational exposure, with an 80% female prevalence due to its use in cosmetic products. Our findings illustrate an unusual polyreactivity of anti-PDC-E2 and support the idea of epitope mimicry in the genesis of this autoantibody and perhaps of PBC itself.

Introduction

The serologic hallmark of primary biliary cirrhosis (PBC), an overwhelmingly female predominant disease, is seropositivity for antimitochondrial antibodies (AMA) directed at the E2 subunits of the 2-oxo-acid dehydrogenase complexes, namely the pyruvate dehydrogenase (PDC-E2), branched-chain 2-oxo-acid dehydrogenase (BCOADC-E2) and oxo-glutarate dehydrogenase (OGDC-E2) [1], [2], [3], [4], [5], [6], [7]. These mitochondrial autoantigens exhibit several shared features including location in the inner mitochondrial matrix, ability to catalyze the oxidative decarboxylation of keto-acid substrates and a common enzyme site which contains a lipoic acid binding domain with lipoic acid covalently attached to a lysine residue. Although the etiology of PBC remains enigmatic, the concept of induction via molecular (epitope) mimicry has been suggested [8], [9], [10], [11], [12].

Our previous work has focused on the hypothesis that a modification of the inner lipoyl domain, located, in particular, either on the lysine or on the lysine-attached lipoic acid co-factor, will lead to loss of tolerance and hence the generation of the antimitochondrial response. This hypothesis was initially based on an analysis of more than 100 structural chemical mimics of lipoic acid and the demonstration that when the lipoyl group of the immunodominant E2 domain of PDC was replaced with specific small molecule conjugates, the ensuing structural mimics displayed specific and very high reactivity with PBC sera [12]. One such compound identified, a 2-octynamide, was the conjugate derived from 2-octynoic acid, and was noted to be present in cosmetics, lipstick and some chewing gums. We have now extended our ability to focus in detail on the optimal chemical structure that leads to enhanced AMA recognition. We report herein, via QSAR, that a newly identified compound, 2-nonynoic acid, provides optimal reactivity and that the methyl ester of this compound is ranked in the top 20% of chemicals with occupational exposure with an 80% female prevalence.

Section snippets

Sera

Analyses was performed on a panel of well-characterized sera from our laboratory, including samples from 21 patients with AMA-positive PBC, 15 with AMA-negative PBC, 12 with primary sclerosing cholangitis (PSC) and 13 healthy subjects. The diagnosis in all cases was verified using published criteria [4], [13]. The AMA status of sera from patients with PBC and controls was determined by ELISA (1:1000 sera dilution) using recombinant mitochondrial autoantigens [14]. The protocol was approved by

Ig reactivity of octynamide conjugates with AMA+ PBC sera

Based on our finding of the unique reactivity of PBC sera with 2-octynamide-PDC-E2 peptide, we sought further to define the role of the triple bond in this class of compounds; we tested well-characterized AMA reactive sera against five different octynamide conjugates with a varying triple bond position. Thus sera from 21 AMA+ PBC patients and 13 controls were analyzed by microarray assay for their relative Ig reactivity with lipoylated or xenobiotic-modified PDC-E2 peptide. Of those compounds,

Discussion

The serologic hallmark of PBC is the presence of antibodies in more than 95% of PBC patients [28] against members of the mitochondrial 2-oxo-acid dehydrogenase complexes, most commonly the pyruvate dehydrogenase E2 complex (PDC-E2) [29]. Such AMA can be found many years before the onset of clinical symptoms of disease [30], [31], suggesting that induction of AMA is related to the onset of PBC. Interestingly, immunization of rabbits and guinea pigs with the lipoic acid mimic 6-bromo-hexanoate,

Acknowledgments

We thank Yan F. Suen for providing some of the chemical compounds used in this study. Supported by National Institutes of Health grants, DK39588 and DK037003.

References (47)

  • J.V. Metcalf et al.

    Natural history of early primary biliary cirrhosis

    Lancet

    (1996)
  • L.Z. Benet et al.

    Predictability of the covalent binding of acidic drugs in man

    Life Sci

    (1993)
  • M. Iwaki et al.

    In vitro regioselective stability of beta-1-O- and 2-O-acyl glucuronides of naproxen and their covalent binding to human serum albumin

    J Pharm Sci

    (1999)
  • J. Olsen et al.

    Identification of the amino acids of human serum albumin involved in the reaction with the naproxen acyl coenzyme A thioester using liquid chromatography combined with fluorescence and mass spectrometric detection

    Anal Biochem

    (2003)
  • A.M. Williams et al.

    Studies on the reactivity of acyl glucuronides—VI. Modulation of reversible and covalent interaction of diflunisal acyl glucuronide and its isomers with human plasma protein in vitro

    Biochem Pharmacol

    (1994)
  • C. Selmi et al.

    Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment

    Gastroenterology

    (2004)
  • R.L. Coppel et al.

    Primary structure of the human M2 mitochondrial autoantigen of primary biliary cirrhosis: dihydrolipoamide acetyltransferase

    Proc Natl Acad Sci USA

    (1988)
  • L. Dubel et al.

    Autoepitope mapping and reactivity of autoantibodies to the dihydrolipoamide dehydrogenase-binding protein (E3BP) and the glycine cleavage proteins in primary biliary cirrhosis

    Hepatology

    (1999)
  • M.M. Kaplan et al.

    Primary biliary cirrhosis

    N Engl J Med

    (2005)
  • M.E. Gershwin et al.

    Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis

    J Immunol

    (1987)
  • D.R. Fregeau et al.

    Inhibition of alpha-ketoglutarate dehydrogenase activity by a distinct population of autoantibodies recognizing dihydrolipoamide succinyltransferase in primary biliary cirrhosis

    Hepatology

    (1990)
  • J. Van de Water et al.

    The autoepitope of the 74-kD mitochondrial autoantigen of primary biliary cirrhosis corresponds to the functional site of dihydrolipoamide acetyltransferase

    J Exp Med

    (1988)
  • C. Selmi et al.

    Bacteria and human autoimmunity: the case of primary biliary cirrhosis

    Curr Opin Rheumatol

    (2004)
  • Cited by (0)

    View full text