Esomeprazole reduces sperm motility index by targeting the spermic cholinergic machinery: A mechanistic study for the association between use of proton pump inhibitors and reduced sperm motility index

Amit Kumar,Rajnish Kumar,John Flanagan,Bengt Långström,Lars Björndahl,Taher Darreh-Shori

doi:10.1016/j.bcp.2020.114212

Amit Kumar, Rajnish Kumar + Show 4 more

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https://doi.org/10.1016/j.bcp.2020.114212

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Abstract

Recent studies have linked prolonged use of the most commonly prescribed proton pump inhibitors (PPIs) with declined human sperm function and infertility. Here, we report for the first time the most plausible underlying mechanism for this unwarranted secondary mode of action. We followed up on a recent serendipitous discovery in our laboratory regarding PPIs’ off-target action and performed detailed pharmacodynamic analyses by combining in silico and in vitro studies to determine the off-target effect of one of the most commonly used PPI, esomeprazole, on the key human acetylcholine biosynthesizing enzyme, choline acetyltransferase (ChAT; EC 2.3.1.6). A pivotal enzyme in the spermic cholinergic system that governs the sperm motility, concentration and quality. Our results were conclusive and showed that both the racemic form, omeprazole and its pure S-enantiomer, esomeprazole, acted as potent mixed-competitive inhibitor of human ChAT with a global inhibition constant (Ki) of 88 nM (95%CI: 10–167 nM) for esomeprazole and 178 nM (95%CI: 140–230 nM) for the racemic drug omeprazole. Most importantly, esomeprazole substantially reduces both total number of motile sperm (by 36%, p < 0.001; and 21% p < 0.0001, at 10 and 100 nM, respectively) as well as the total number of sperm with progressive motility (by 42% p < 0.0016 and by 26% p < 0.0001, respectively) after 60 min relative to 20 min incubation in our ex vivo functional assay performed on ejaculated human sperm. In conclusion, this study presents a completely new perspective regarding PPIs secondary mode of action/unwarranted side effects and calls for further mechanistic and larger clinical studies to elucidate the role of PPIs in infertility.

Highlights

The cholinergic signaling system is believed to have been developed during very early evolutionary stages of life as the key classical neu rotransmitter acetylcholine (ACh) has been observed in all forms of life and widely synthesized and used by neuronal non-neuronal cells [1]
Our analyses indicated that the binding pocket for esomeprazole lies inside the catalytic tunnel of choline acetyltransferase (ChAT) and almost overlaps the A-CoA/CoA binding site
We followed up a recent serendipitous dis covery in our laboratory concerning an unprecedented secondary mode of action of pump inhibitors (PPIs), namely inhibition of the key cholinergic enzyme ChAT

Summary

Introduction

The cholinergic signaling system is believed to have been developed during very early evolutionary stages of life as the key classical neu rotransmitter acetylcholine (ACh) has been observed in all forms of life and widely synthesized and used by neuronal non-neuronal cells [1]. The expression and activity of ACh-biosynthesizing enzyme, choline acetyltransferase (ChAT) (EC: 2.3.1.6; Choline O-acetyltransferase) defines cholinergic neurons/cells. The enzymes acet ylcholinesterase (AChE) and butyrylcholinesterase (BChE), which break down ACh and abolish neurotransmission, are expressed by the downstream cholinoceptive cells/neurons as well as in soluble forms in whole blood, plasma, cerebrospinal fluids and interstitial fluids [2]. The role of the central cholinergic system in cognition is well-es tablished [3] and its early and selective degeneration is considered one of the hallmarks of Alzheimer’s disease, Lewy body dementias (DLB, including dementia with Lewy body and Parkinson’s dementia) and Down’s syndrome [4,5,6,7]

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