d‐Penicillamine modulates hydrogen sulfide (H₂S) pathway through selective inhibition of cystathionine‐γ‐lyase

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.

DOI: 10.1111/bph.13459

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