title: Electrophilicities and Protein Covalent Binding of Demethylation Metabolites of Colchicine.
abstract: Colchicine, an alkaloid existing in plants of Liliaceous colchicum, has been widely used in the treatment of gout and familial Mediterranean fever. The administration of colchicine was found to cause liver injury in humans. The mechanisms of colchicine-induced liver toxicity remain unknown. The objectives of this study were to determine the electrophilicities of demethylation metabolites of colchicine and investigate the protein adductions derived from the reactive metabolites of colchicine. Four demethylated colchicine (1-, 2-, 3-, and 10-DMCs), namely, M1-M4, were detected in colchicine-fortified microsomal incubations. Four N-acetyl cysteine (NAC) conjugates (M5-M8) derived from colchicine were detected in the microsomes in the presence of NAC. M5 and M6 were derived from 10-DMC. M7 resulted from the reaction of 2-DMC or 3-DMC with NAC, and M8 originated from 10-DMC. Microsomal protein covalent binding was observed after exposure to colchicine. Two cysteine adducts (CA-1 and CA-2) derived from 10-DMC were found in proteolytically digested microsomal protein samples after incubation with colchicine. The findings allow us to define the chemical property of demethylation metabolites of colchicine and the interaction between protein and the reactive metabolites of colchicine generated in situ.
authors: Xiucai
authors: X
authors: Guo
authors: Dongju
authors: D
authors: Lin
authors: Weiwei
authors: W
authors: Li
authors: Kai
authors: K
authors: Wang
authors: Ying
authors: Y
authors: Peng
authors: Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine , Seattle, Washington 98101, United States.
authors: Jiang
authors: J
authors: Zheng
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D003078:Colchicine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008745:Methylation / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002352:Carrier Proteins; D003078:Colchicine