Molecular Basis for the Interaction of Catalase with D-Penicillamine : Rationalization of some of its Deleterious Effects

Abstract

D-penicillamine (D-Pen) is a sulfur compound used in the management of rheumatoid arthritis, Wilsons disease (WD), and alcohol dependence. Many side effects are associated with its use, particularly after long-term treatment. However, the molecular bases for such side effects are poorly understood. Based on the well-known oxidase activity of hemoproteins, and the participation of catalase in cellular H2O2 redox signaling, we posit that D-Pen could inactivate catalase, thus disturbing H2O2 levels. Herein, we report on the molecular bases that could partly explain the side effects associated with this drug compound, and we demonstrate that it induces the formation of compound II, a temporarily inactive state of the enzyme, through two distinct mechanisms. Initially, D-Pen reacts with native catalase and/or iron metal ions, used to mimic non heme iron overload observed in long-term treated WD patients, to generate thiyl radicals. These partake into a futile redox cycling, thus producing superoxide radical anions O2*- and hydrogen peroxide H2O2. Then, either H2O2 unexpectedly reacts with native CAT-Fe(II) to produce compound II, or both aforementioned reactive oxygen species intervene into compound II generation through compound I formation then reduction. These findings support evidence that D-Pen could perturb H2O2 redox homeostasis through transient but recurring catalase inactivation, which may in part rationalize some deleterious effects observed with this therapeutic agent, as discussed. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/460603v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@f1111dorg.highwire.dtl.DTLVardef@9a8b81org.highwire.dtl.DTLVardef@3cc797org.highwire.dtl.DTLVardef@539f24_HPS_FORMAT_FIGEXP M_FIG C_FIG