title: D-Penicillamine modulates hydrogen sulfide (H2S) pathway through selective inhibition of cystathionine-γ-lyase.
abstract: OBJECTIVE
  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. AsD-penicillamine is structurally very similar to cysteine, we have investigated whether D-penicillamine, as a cysteine analogue, has an effect on the H2 S pathway.
  
  
  METHODS
  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 H2 S biosynthesis. In particular, we investigated any possible inhibitor or donor behaviour by using recombinant enzyme-based assays and an in vivo approach.
  
  
  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 H2 S biosynthesis, and this effect occurred at concentrations 10 times lower than those needed to induce the release of H2 S. In particular, D-penicillamine selectively inhibited CSE in a pyridoxal-5'-phosphate-dependent manner.
  
  
  CONCLUSIONS
  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 H2 S research. In addition, the inhibitory effect of D-penicillamine on CSE could account for its beneficial action in rheumatoid arthritis patients, where H2 S has been shown to have a detrimental effect.
authors.affiliation: Department of Science, University of Basilicata, Potenza, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Brancaleone
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Gargiulo
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vellecco
authors.affiliation: Department of Pharmacy, University of Patras, Patras, Greece.
authors.forename: Antonia
authors.initials: A
authors.lastname: Asimakopoulou
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Citi
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.affiliation: William Harvey Research Institute, Queen Mary University of London, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gobbetti
authors.affiliation: William Harvey Research Institute, Queen Mary University of London, London, UK.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.affiliation: Faculty of Pharmacy, University of Athens, Athens, Greece.
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
mesh_terms: D000818:Animals; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D051379:Mice; D010396:Penicillamine / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D003542:Cystathionine gamma-Lyase; D010396:Penicillamine; D006862:Hydrogen Sulfide