Mechanism of biochemical action of substituted 4-methylbenzopyran-2-ones. Part 3: A novel mechanism for the inhibition of biological membrane lipid peroxidation by dioxygenated 4-methylcoumarins mediated by the formation of a stable ADP-Fe-inhibitor mixed ligand complex.
7,8-Dihydroxy-4-methylcoumarin (DHMC) and 7,8-diacetoxy-4-methylcoumarin (DAMC) have been reported to effectively inhibit in-vivo lipid peroxidation in rat tissues induced by CCl4 and paraquat. DHMC was found to readily impart green colour to the lipid peroxidation incubation mixture containing ADP and Fe3+, whereas DAMC formed green complex only upon incubation with liver microsomes, confirming our earlier observation that liver microsomal deacetylase hydrolyses DAMC to DHMC. Sensitive pH metric technique revealed the formation of ADP-Fe-DHMC ternary complex with highest stability, while Fe-DHMC and ADP-DHMC had negligible stabilities concluding that ADP-perferryl ion formation is prevented by DHMC resulting in the production of stable ternary mixed ligand complex (ADP-Fe-DHMC), thereby inhibiting the formation of O2-, and eventually other reactive oxygen species (ROS) responsible for membrane lipid peroxidation.
Raj
H G
HG
Department of Biochemistry, University of Delhi, India.
Sharma
R K
RK
Garg
B S
BS
Parmar
V S
VS
Jain
S C
SC
Goel
S
S
Tyagi
Y K
YK
Singh
A
A
Olsen
C E
CE
Wengel
J
J
D000244:Adenosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002251:Carbon Tetrachloride / Q000633:toxicity; D003374:Coumarins / Q000494:pharmacology*; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D015227:Lipid Peroxidation / Q000187:drug effects*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010269:Paraquat / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
C114369:7,8-diacetoxy-4-methylcoumarin; C114368:7,8-dihydroxy-4-methylcoumarin; D000975:Antioxidants; D003374:Coumarins; D008024:Ligands; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; D000244:Adenosine Diphosphate; D002251:Carbon Tetrachloride; D007501:Iron; D010269:Paraquat