title: alpha-Lipoic acid and glutathione protect against the prooxidant activity of SOD/catalase mimetic manganese salen derivatives.
abstract: Manganese(III) N,N'-ethylenebis(salicylideneiminato) chloride (Mn-salen chloride) and manganese(III) N,N'-ethylenebis(3-methoxysalicylideneiminato) chloride (Mn-(3,3'-MeO)salen chloride) are in vitro superoxide dismutase and catalase mimetics. They protect against free radical-related disease in animals, but Mn-salen can also be a potent prooxidant, damaging free DNA. Mn-salen protects human fibroblast DNA against hydrogen peroxide damage, however, damage to free DNA was confirmed by the comet assay. The DNA-damaging activity was dramatically reduced by co-administration with glutathione with the combination being less damaging to free DNA than either molecule alone. alpha-Lipoic acid, an antioxidant disulfide commonly used as a dietary supplement, also prevented Mn-salen prooxidant activity. Mn-(3,3'-MeO)salen protected fibroblasts against hydrogen peroxide as efficiently as Mn-salen and showed little damaging activity against free DNA. Protection was invested by both complexes in the presence and in the absence of EDTA, a potential competing chelator. Stabilities of the complexes with respect to decomposition and inactivation were studied by spectroscopic and electrochemical techniques. The complexes' binding to, and cleavage of, DNA was measured using a quartz crystal resonant sensor. Mn-salen was shown to bind strongly to DNA, prior to cleaving it; Mn-(3,3'-MeO)salen bound weakly and left DNA intact. Co-administration of either glutathione or alpha-lipoic acid appears to inhibit binding by Mn-salen thus preventing DNA-cleavage.
authors.affiliation: School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Lewes Road, Moulsecoomb, Brighton BN2 4GJ, UK.
authors.forename: Flavia
authors.initials: F
authors.lastname: Fucassi
authors.forename: Jillian E
authors.initials: JE
authors.lastname: Lowe
authors.forename: Karl D
authors.initials: KD
authors.lastname: Pavey
authors.forename: Seema
authors.initials: S
authors.lastname: Shah
authors.forename: Richard G A
authors.initials: RG
authors.lastname: Faragher
authors.forename: Michael H L
authors.initials: MH
authors.lastname: Green
authors.forename: Frank
authors.initials: F
authors.lastname: Paul
authors.forename: Danny
authors.initials: D
authors.lastname: O'Hare
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cragg
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism*; D002478:Cells, Cultured; D020552:Comet Assay; D004249:DNA Damage; D004563:Electrochemistry; D005029:Ethylenediamines / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000494:pharmacology*; D006801:Humans; D017895:Manganese Compounds / Q000737:chemistry / Q000494:pharmacology; D018716:Molecular Mimicry; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D016877:Oxidants / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D005029:Ethylenediamines; D017895:Manganese Compounds; D009942:Organometallic Compounds; D016877:Oxidants; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II); D008063:Thioctic Acid; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione