title: Aminoacylase 1-catalysed deacetylation of bioactives epoxides mycotoxin-derived mercapturates; 3,4-epoxyprecocenes as models of cytotoxic epoxides.
abstract: The mycotoxin aflatoxin B1 (AFB1) is a carcinogenic food contaminant which is metabolically activated by epoxydation. The metabolism of mycotoxins via the mercapturate metabolic pathway was shown, in general, to lead to their detoxication. Mercapturic acids thus formed (S-substitued-N-acetyl-l-cysteines) may be accumulated in the kidney and either excreted in the urine or desacetylated by Acylase 1 (ACY1) to yield cysteine S-conjugates. To be toxic, the N-acetyl-l-cysteine-S-conjugates first have to undergo deacetylation by ACY 1. The specificity and rate of mercapturic acid deacetylation may determine the toxicity, however the exact deacetylation processes involved are not well known. The aim of this study was to investigate the role of ACY1 in the toxicity of some bioactive epoxides from Aflatoxin B1. We characterized the kinetic parameters of porcine kidney and human recombinant aminoacylase-1 towards some aromatic and aliphatic-derived mercapturates analogue of mycotoxin-mercapturic acids and 3,4-epoxyprecocene, a bioactive epoxide derivated from aflatoxin. The deacetylation of mercapturated substrates was followed both by reverse phase HPLC and by TNBS method. Catalytic activity was discussed in a structure-function relationship. Ours results indicate for the first time that aminoacylase-1 could play an important role in deacetylating mercapturate metabolites of aflatoxin analogues and this process may be in relation with their cyto- and nephrotoxicity in human.
authors.affiliation: Aix-Marseille Univ., ISM2-BiosCiences UMR-6263 CNRS, Faculté des Sciences, 13397 Marseille Cedex 20, France. p.stocker@univ.cezanne.fr
authors.forename: Pierre
authors.initials: P
authors.lastname: Stocker
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Brunel
authors.forename: Leandro
authors.initials: L
authors.lastname: de Rezende
authors.forename: Antonia Tavares
authors.initials: AT
authors.lastname: do Amaral
authors.forename: Xavier
authors.initials: X
authors.lastname: Morelli
authors.forename: Phillipe
authors.initials: P
authors.lastname: Roche
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vidal
authors.forename: Thierry
authors.initials: T
authors.lastname: Giardina
authors.forename: Josette
authors.initials: J
authors.lastname: Perrier
mesh_terms: D000107:Acetylation; D000111:Acetylcysteine / Q000737:chemistry*; D016604:Aflatoxin B1 / Q000737:chemistry; D000581:Amidohydrolases / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001578:Benzopyrans / Q000737:chemistry; D002384:Catalysis; D004852:Epoxy Compounds / Q000737:chemistry*; D006801:Humans; D008658:Inactivation, Metabolic; D007668:Kidney / Q000201:enzymology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine
chemical_list: D001578:Benzopyrans; D004852:Epoxy Compounds; D016604:Aflatoxin B1; D000581:Amidohydrolases; C019672:aminoacylase I; D000111:Acetylcysteine