D -Penicillamine modulates hydrogen sulfide (H2S) pathway through selective inhibition of cystathionine-γ-lyase

Vincenzo Brancaleone, Iolanda Esposito, Antonella Gargiulo, Valentina Vellecco, Antonia Asimakopoulou, Valentina Citi, Vincenzo Calderone, Thomas Gobbetti, Mauro Perretti, Andreas Papapetropoulos, Mariarosaria Bucci, Giuseppe Cirino

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background and Purpose Hydrogen sulfide (H2S) is a gasotransmitter produced from l-cysteine through the enzymatic action of cystathionine-γ-lyase (CSE) and/or cystathionine-β-synthase. d-Penicillamine is the d isomer of a dimethylated cysteine and has been used for the treatment of rheumatoid arthritis. As d-penicillamine is structurally very similar to cysteine, we have investigated whether d-penicillamine, as a cysteine analogue, has an effect on the H2S pathway. Experimental Approach We tested the effect of d-penicillamine (0.01-1 mM) in mouse aortic rings mounted in isolated organ baths and determined whether it could affect H2S biosynthesis. In particular, we investigated any possible inhibitor or donor behaviour by using recombinant enzyme-based assays and an in vivo approach. Key Results d-Penicillamine, per se, showed little or no vasodilator effect, and it cannot be metabolized as a substrate in place of l-cysteine. However, d-penicillamine significantly reduced l-cysteine-induced vasodilatation in a concentration-dependent manner through inhibition of H2S biosynthesis, and this effect occurred at concentrations 10 times lower than those needed to induce the release of H2S. In particular, d-penicillamine selectively inhibited CSE in a pyridoxal-5′-phospate-dependent manner. Conclusions and Implications Taken together, our results suggest that d-penicillamine acts as a selective CSE inhibitor, leading to new perspectives in the design and use of specific pharmacological tools for H2S research. In addition, the inhibitory effect of d-penicillamine on CSE could account for its beneficial action in rheumatoid arthritis patients, where H2S has been shown to have a detrimental effect.

Original languageEnglish (US)
Pages (from-to)1556-1565
Number of pages10
JournalBritish Journal of Pharmacology
Volume173
Issue number9
DOIs
StatePublished - May 1 2016
Externally publishedYes

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Cystathionine
Hydrogen Sulfide
Lyases
Penicillamine
Cysteine
Rheumatoid Arthritis
Gasotransmitters
Pyridoxal
Inhibition (Psychology)
Enzyme Assays
Vasodilator Agents
Baths
Vasodilation
Tissue Donors
Pharmacology

ASJC Scopus subject areas

  • Pharmacology

Cite this

Brancaleone, V., Esposito, I., Gargiulo, A., Vellecco, V., Asimakopoulou, A., Citi, V., ... Cirino, G. (2016). D -Penicillamine modulates hydrogen sulfide (H2S) pathway through selective inhibition of cystathionine-γ-lyase. British Journal of Pharmacology, 173(9), 1556-1565. https://doi.org/10.1111/bph.13459

D -Penicillamine modulates hydrogen sulfide (H2S) pathway through selective inhibition of cystathionine-γ-lyase. / Brancaleone, Vincenzo; Esposito, Iolanda; Gargiulo, Antonella; Vellecco, Valentina; Asimakopoulou, Antonia; Citi, Valentina; Calderone, Vincenzo; Gobbetti, Thomas; Perretti, Mauro; Papapetropoulos, Andreas; Bucci, Mariarosaria; Cirino, Giuseppe.

In: British Journal of Pharmacology, Vol. 173, No. 9, 01.05.2016, p. 1556-1565.

Research output: Contribution to journalArticle

Brancaleone, V, Esposito, I, Gargiulo, A, Vellecco, V, Asimakopoulou, A, Citi, V, Calderone, V, Gobbetti, T, Perretti, M, Papapetropoulos, A, Bucci, M & Cirino, G 2016, 'D -Penicillamine modulates hydrogen sulfide (H2S) pathway through selective inhibition of cystathionine-γ-lyase', British Journal of Pharmacology, vol. 173, no. 9, pp. 1556-1565. https://doi.org/10.1111/bph.13459
Brancaleone, Vincenzo ; Esposito, Iolanda ; Gargiulo, Antonella ; Vellecco, Valentina ; Asimakopoulou, Antonia ; Citi, Valentina ; Calderone, Vincenzo ; Gobbetti, Thomas ; Perretti, Mauro ; Papapetropoulos, Andreas ; Bucci, Mariarosaria ; Cirino, Giuseppe. / D -Penicillamine modulates hydrogen sulfide (H2S) pathway through selective inhibition of cystathionine-γ-lyase. In: British Journal of Pharmacology. 2016 ; Vol. 173, No. 9. pp. 1556-1565.
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AU - Asimakopoulou, Antonia

AU - Citi, Valentina

AU - Calderone, Vincenzo

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