Human dimethylarginine dimethylaminohydrolase 1 inhibition by proton pump inhibitors and the cardiovascular risk marker asymmetric dimethylarginine: in vitro and in vivo significance.

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Tommasi S, Elliot DJ, Hulin JA, Lewis BC, McEvoy M, Mangoni AA

Human dimethylarginine dimethylaminohydrolase 1 inhibition by proton pump inhibitors and the cardiovascular risk marker asymmetric dimethylarginine: in vitro and in vivo significance.

Sci Rep. 2017 Jun 6;7(1):2871. doi: 10.1038/s41598-017-03069-1.

PubMed ID

28588208 [ View in PubMed

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Abstract

Proton pump inhibitor (PPI)-induced inhibition of dimethylarginine dimethylaminohydrolase 1 (DDAH1), with consequent accumulation of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA), might explain the increased cardiovascular risk with PPI use. However, uncertainty exists regarding whether clinical PPI concentrations significantly inhibit DDAH1 under linear initial rate conditions, and whether PPI-induced DDAH1 inhibition significantly increases ADMA in humans. DDAH1 inhibition by esomeprazole, omeprazole, pantoprazole, lansoprazole and rabeprazole was determined by quantifying DDAH1-mediated L-citrulline formation in vitro. Plasma ADMA was measured in PPI users (n = 134) and non-users (n = 489) in the Hunter Community Study (HCS). At clinical PPI concentrations (0.1-10 mumol/L), DDAH1 retained >80% activity vs. baseline. A significant, reversible, time-dependent inhibition was observed with lansoprazole (66% activity at 240 min, P = 0.034) and rabeprazole (25% activity at 240 min, P < 0.001). In regression analysis, PPI use was not associated with ADMA in HCS participants (beta 0.012, 95% CI -0.001 to 0.025, P = 0.077). Furthermore, there were no differences in ADMA between specific PPIs (P = 0.748). At clinical concentrations, PPIs are weak, reversible, DDAH1 inhibitors in vitro. The lack of significant associations between PPIs and ADMA in HCS participants questions the significance of DDAH1 inhibition as a mechanism explaining the increased cardiovascular risk reported with PPI use.

DrugBank Data that Cites this Article

Drugs

Pantoprazole

Esomeprazole

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Dexlansoprazole	N(G),N(G)-dimethylarginine dimethylaminohydrolase 1	Protein	Humans	Unknown	Not Available	Details
Esomeprazole	N(G),N(G)-dimethylarginine dimethylaminohydrolase 1	Protein	Humans	Unknown	Not Available	Details
Pantoprazole	N(G),N(G)-dimethylarginine dimethylaminohydrolase 1	Protein	Humans	No	Inhibitor	Details