Abstract：
BACKGROUND/AIMS:Carnitine palmitoyl-transferase I (CPT I) catalyses the synthesis of long-chain (LC)-acylcarnitines from LC-acyl-CoA esters. It is the rate-limiting enzyme of mitochondrial fatty acid beta-oxidation (FAO) pathway and its activity is regulated by malonyl-CoA. The antiepileptic drug valproic acid (VPA) is a branched chain fatty acid that is activated to the respective CoA ester in the intra- and extra-mitochondrial compartments. This drug has been associated with a clear inhibition of mitochondrial FAO, which motivated our study on its potential effect on hepatic CPT I. METHODS:To investigate the effect of valproyl-CoA (VP-CoA) on CPT I, we performed in vitro studies using control human fibroblasts and rat CPT IA expressed in Saccharomyces cerevisiae. In addition to the wild-type enzyme, two mutant rCPT IAs were studied, one of which showing increased sensitivity towards malonyl-CoA (S24A/Q30A), whereas the other one is insensitive to malonyl-CoA (E3A). RESULTS:We demonstrate that VP-CoA inhibits the CPT I activity in control fibroblasts. Similar results were obtained using rCPT IA WT and S24A/Q30A. Importantly, VP-CoA also inhibited the activity of the rCPT IA E3A. We show that VP-CoA inhibits CPT IA competitively with respect to palmitoyl-CoA, and non-competitively to carnitine. Evidence is provided that VP-CoA interferes at the catalytic domain of CPT IA affecting the sensitivity for malonyl-CoA. CONCLUSIONS:The interference of VP-CoA with CPT IA, a pivotal enzyme in mitochondrial fatty acid beta-oxidation, may be a crucial mechanism in the drug-induced hepatotoxicity and the weight gain frequently observed in patients under VPA therapy.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Aires CC,Ijlst L,Stet F,Prip-Buus C,de Almeida IT,Duran M,Wanders RJ,Silva MFdoi
10.1016/j.bcp.2009.10.011subject
Has Abstractpub_date
2010-03-01 00:00:00pages
792-9issue
5eissn
0006-2952issn
1873-2968pii
S0006-2952(09)00905-8journal_volume
79pub_type
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