PubMed:23402341 JSONTXT

{"project":"Allie","denotations":[{"id":"SS1_23402341_1_0","span":{"begin":76,"end":91},"obj":"expanded"},{"id":"SS2_23402341_1_0","span":{"begin":93,"end":96},"obj":"abbr"},{"id":"SS1_23402341_1_1","span":{"begin":128,"end":163},"obj":"expanded"},{"id":"SS2_23402341_1_1","span":{"begin":165,"end":170},"obj":"abbr"},{"id":"SS1_23402341_1_2","span":{"begin":228,"end":252},"obj":"expanded"},{"id":"SS2_23402341_1_2","span":{"begin":254,"end":263},"obj":"abbr"},{"id":"SS1_23402341_1_3","span":{"begin":269,"end":283},"obj":"expanded"},{"id":"SS2_23402341_1_3","span":{"begin":285,"end":292},"obj":"abbr"},{"id":"SS1_23402341_1_4","span":{"begin":341,"end":363},"obj":"expanded"},{"id":"SS2_23402341_1_4","span":{"begin":365,"end":372},"obj":"abbr"},{"id":"SS1_23402341_8_0","span":{"begin":1611,"end":1636},"obj":"expanded"},{"id":"SS2_23402341_8_0","span":{"begin":1638,"end":1641},"obj":"abbr"}],"relations":[{"id":"AE1_23402341_1_0","pred":"abbreviatedTo","subj":"SS1_23402341_1_0","obj":"SS2_23402341_1_0"},{"id":"AE1_23402341_1_1","pred":"abbreviatedTo","subj":"SS1_23402341_1_1","obj":"SS2_23402341_1_1"},{"id":"AE1_23402341_1_2","pred":"abbreviatedTo","subj":"SS1_23402341_1_2","obj":"SS2_23402341_1_2"},{"id":"AE1_23402341_1_3","pred":"abbreviatedTo","subj":"SS1_23402341_1_3","obj":"SS2_23402341_1_3"},{"id":"AE1_23402341_1_4","pred":"abbreviatedTo","subj":"SS1_23402341_1_4","obj":"SS2_23402341_1_4"},{"id":"AE1_23402341_8_0","pred":"abbreviatedTo","subj":"SS1_23402341_8_0","obj":"SS2_23402341_8_0"}],"text":"Characterization of the acyl-adenylate linked metabolite of mefenamic Acid.\nMefenamic acid, (MFA), a carboxylic acid-containing nonsteroidal anti-inflammatory drug (NSAID), is metabolized into the chemically reactive conjugates MFA-1-O-acyl-glucuronide (MFA-1-O-G) and MFA-S-acyl-CoA (MFA-CoA), which are both implicated in the formation of MFA-S-acyl-glutathione (MFA-GSH) conjugates, protein-adduct formation, and thus the potential toxicity of the drug. However, current studies suggest that an additional acyl-linked metabolite may be implicated in the formation of MFA-GSH. In the present study, we investigated the ability of MFA to become bioactivated into the acyl-linked metabolite, mefenamyl-adenylate (MFA-AMP). In vitro incubations in rat hepatocytes with MFA (100 μM), followed by LC-MS/MS analyses of extracts, led to the detection of MFA-AMP. In these incubations, the initial rate of MFA-AMP formation was rapid, leveling off at a maximum concentration of 90.1 nM (20 s), while MFA-GSH formation increased linearly, reaching a concentration of 1.7 μM after 60 min of incubation. In comparison, MFA-CoA was undetectable in incubation extracts until the 4 min time point, achieving a concentration of 45.6 nM at the 60 min time point, and MFA-1-O-G formation was linear, attaining a concentration of 42.2 μM after 60 min of incubation. In vitro incubation in buffer with the model nucleophile glutathione (GSH) under physiological conditions showed MFA-AMP to be reactive toward GSH, but 11-fold less reactive than MFA-CoA, while MFA-1-O-G exhibited little reactivity. However, in the presence of glutathione-S-transferase (GST), MFA-AMP mediated formation of MFA-GSH increased 6-fold, while MFA-CoA mediated formation of MFA-GSH only increased 1.4-fold. Collectively, in addition to the MFA-1-O-G, these results demonstrate that mefenamic acid does become bioactivated by acyl-CoA synthetase enzyme(s) in vitro in rat hepatocytes into the reactive transacylating derivatives MFA-AMP and MFA-CoA, both of which contribute to the transacylation of GSH and may be involved in the formation of protein adducts and potentially elicit an idiosyncratic toxicity."}

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