PMID: 9645388Jun 30, 1998Paper

The oxidative inactivation of tissue inhibitor of metalloproteinase-1 (TIMP-1) by hypochlorous acid (HOCI) is suppressed by anti-rheumatic drugs

Free Radical Research
F ShabaniL Tippett

Abstract

Tissue inhibitors of metalloproteinases (TIMPs) prevent uncontrolled connective tissue destruction by limiting the activity of matrix metalloproteinases (MMPs). That TIMPs should be susceptible to oxidative inactivation is suggested by their complex tertiary structure which is dependent upon 6 disulphide bonds. We examined the oxidative inactivation of human recombinant TIMP-1 (hr TIMP-1) by HOCl and the inhibition of this process by anti-rheumatic agents. TIMP-1 was exposed to HOCl in the presence of a variety of disease modifying anti-rheumatic drugs. TIMP-1 activity was measured by its ability to inhibit BC1 collagenase activity as measured by a fluorimetric assay using the synthetic peptide substrate (DNP-Pro-Leu-Ala-Leu-Trp-Ala-Arg), best cleaved by MMP-1. The neutrophil derived oxidant HOCl, but not the derived oxidant N-chlorotaurine, can inactivate TIMP-1 at concentrations achieved at sites of inflammation. Anti-rheumatic drugs have the ability to protect hrTIMP-1 from inactivation by HOCl. For D-penicillamine, this effect occurs at plasma levels achieved with patients taking the drug but for other anti-rheumatic drugs tested this occurs at relatively high concentrations that are unlikely to be achieved in vivo, except ...Continue Reading

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