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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.
Kumar, Amit; Kumar, Rajnish; Flanagan, John; Långström, Bengt; Björndahl, Lars; Darreh-Shori, Taher.
Afiliação
  • Kumar A; Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. Electronic address: amit.kumar@ki.se.
  • Kumar R; Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
  • Flanagan J; ANOVA, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
  • Långström B; Department of Chemistry, Uppsala University, Uppsala, Sweden.
  • Björndahl L; ANOVA, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Darreh-Shori T; Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. Electronic address: Taher.Darreh-Shori@ki.se.
Biochem Pharmacol ; 182: 114212, 2020 12.
Article em En | MEDLINE | ID: mdl-32866455
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.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Motilidade dos Espermatozoides / Colina O-Acetiltransferase / Inibidores da Bomba de Prótons / Esomeprazol Tipo de estudo: Risk_factors_studies Limite: Adult / Humans / Male Idioma: En Revista: Biochem Pharmacol Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Motilidade dos Espermatozoides / Colina O-Acetiltransferase / Inibidores da Bomba de Prótons / Esomeprazol Tipo de estudo: Risk_factors_studies Limite: Adult / Humans / Male Idioma: En Revista: Biochem Pharmacol Ano de publicação: 2020 Tipo de documento: Article