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Derivatives of 1,4‐dihydropyridines as modulators of ascorbate‐induced lipid peroxidation and high‐amplitude swelling of mitochondria, caused by ascorbate, sodium linoleate and sodium pyrophosphate
Author(s) -
Velēna Astrīda,
Zilbers Juris,
Duburs Gunārs
Publication year - 1999
Publication title -
cell biochemistry and function
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.933
H-Index - 61
eISSN - 1099-0844
pISSN - 0263-6484
DOI - 10.1002/(sici)1099-0844(199912)17:4<237::aid-cbf836>3.0.co;2-k
Subject(s) - chemistry , ascorbic acid , dhps , lipid peroxidation , swelling , antioxidant , mitochondrion , stereochemistry , biochemistry , medicinal chemistry , food science , chemical engineering , malaria , immunology , plasmodium falciparum , biology , engineering
A group of 26 2,6‐dimethyl‐3,5‐disubstituted and 2,6‐dimethyl‐3,4,5‐trisubstituted‐1,4‐dihydropyridines (1,4‐H 2 Py=1,4‐DHPs) and five related pyridines were studied as inhibitors of rat liver mitochondrial swelling and O 2 uptake by ascorbic acid‐dependent lipid peroxidation (LP) and as modulators of mitochondrial swelling induced by Na + ‐linoleate or Na + ‐pyrophosphate. 1,4‐DHPs studied include 4‐unsubstituted and 4‐methyl‐ and 4‐phenyl‐substituted 3,5‐dialkoxycarbonylderivatives of 2,6‐dimethyl‐1,4‐DHP with variations in alkoxy chain length and composition, 4‐unsubstituted and 4‐methyl‐, 4‐aryl‐ and 4‐pyridyl‐substituted 3,5‐dianilidocarbonylderivatives, and a structurally related group of 3,5‐dipyridylamidocarbonylderivatives. Many 1,4‐DHPs possess marked antioxidant (AO) and membrane stabilizing activity, expressed as the mitochondrial swelling (δA 520 /t) and/or O 2 uptake rate decrease (V 0 /V) as well as prolongation of the induction period (τ/τ 0 ) of mitochondrial swelling and/or O 2 uptake at ascorbic acid‐dependent LP of rat liver mitochondria. 4‐Unsubstituted 3,5‐dialkoxycarbonyl‐2,6‐dimethyl‐1,4‐DHPs, as well as 4‐unsubstituted or those possessing lipophylic 4‐aryl‐ groups 3,5‐diamido‐2,6‐dimethyl‐1,4‐DHPs, reveal marked AO and membrane stabilizing properties. Oxidized (heteroaromatized) derivatives have minimal activity. Perhaps 1,4‐DHPs preferably act as antioxidants on stages of initiation and prolongation of LP chain reactions at low concentrations: IC 50 (when V 0 /V or τ/τ 0 =2) are 0·1 µ m to 100 µ m . At 100 µ m 3,5‐di‐ p ‐hydroxyphenoxycarbonyl‐ and 3,5‐di‐ p ‐tolyloxycarbonyl‐2,6‐dimethyl‐1,4‐DHPs, as well as 3,5‐diethoxycarbonyl‐2,6‐dimethylpyridine (oxidized form of Hantzsch ester) and 3,5‐diamyloxycarbonyl‐2,6‐dimethylpyridine, alter the mitochondrial swelling rate in the presence of natural protonophore Na + ‐linoleate (0·063 m m and 0·125 m m ). 3,5‐Di‐ n ‐butyloxycarbonyl‐2,6‐dimethyl‐1,4‐DHP at 100 µ m completely stops mitochondrial swelling in the presence of 0·8 m m Na + ‐pyrophosphate. In the presence of many of the 1,4‐DHPs, the lipid peroxidation process was inhibited. However, the swelling process could be prolonged, promoted, accelerated or inhibited—depending on 1,4‐DHPs structure, concentration, the type of initiators of the swelling process and the medium composition. Copyright © 1999 John Wiley & Sons, Ltd.