Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis
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)
- et al.
Autoantibodies to BCOADC-E2 in patients with primary biliary cirrhosis recognize a conformational epitope
Hepatology
(1995) - et al.
Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium
Hepatology
(2003) - et al.
Autoreactivity to lipoate and a conjugated form of lipoate in primary biliary cirrhosis
Gastroenterology
(2003) - et al.
Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community
Gastroenterology
(2003) - et al.
Use of a designer triple expression hybrid clone for three different lipoyl domain for the detection of antimitochondrial autoantibodies
Hepatology
(1996) - et al.
Bromide-free TEMPO-mediated oxidation of primary alcohol groups in starch and methyl a-D-glucopyranoside
Carbohydrate Research
(2000) - et al.
Chemoselective ligation reactions with proteins, oligosaccharides and cells
Trends Biotechnol
(1998) - et al.
Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides
Anal Biochem Field
(1970) - et al.
visual molecular dynamics
J Mol Graph
(1996) - et al.
Antimitochondrial and other autoantibodies
Clin Liver Dis
(2003)