Nitroaryl-1,4-dihydropyridines as antioxidants against rat liver microsomes oxidation induced by iron/ascorbate, nitrofurantoin and naphthalene.
1,4-Dihydropyridines (DHPs) used in the treatment of cardiovascular diseases, are calcium channel antagonists and also antioxidant agents. These drugs are metabolized through cytochrome P(450) oxidative system, majority localized in the hepatic endoplasmic reticulum. Several lipophilic drugs generate oxidative stress to be metabolized by this cellular system. Thus, DHP antioxidant properties may prevent the oxidative stress associated with hepatic biotransformation of drugs. In this work, we tested the antioxidant capacity of several synthetic nitro-phenyl-DHPs. These compounds (I-IV) inhibited the microsomal lipid peroxidation, UDPGT oxidative activation and microsomal thiols oxidation; all phenomena induced by Fe(3+)/ascorbate, a generator system of oxygen free radicals. As the same manner, these compounds inhibited the oxygen consumption induced by Cu(2+)/ascorbate in the absence of microsomes. Furthermore, compound III (2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridin-3,5-ethyl-dicarboxylate) and compound V (N-ethyl-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridin-3,5-methyl-dicarboxylate) inhibited the microsomal lipid peroxidation induced by Nitrofurantoin and naphthalene in the presence of NADPH. Oxidative stress induced on endoplasmic reticulum may alter the biotransformation of drugs, so, modifying their plasmatic concentrations and therapeutic effects. When drugs which are activated by biotransformation are administered together with antioxidant drugs, such as DHPs, oxidative stress induced in situ may be prevented.
Laboratory of Pharmacology, Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Olivos 1007, Independencia, Santiago, Chile. mel@ciq.uchile.cl
María Eugenia
ME
Letelier
Paz
P
Entrala
Camilo
C
López-Alarcón
Víctor
V
González-Lira
Alfredo
A
Molina-Berríos
Juan
J
Cortés-Troncoso
José
J
Jara-Sandoval
Paola
P
Santander
Luis
L
Núñez-Vergara
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000633:toxicity*; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation; D014453:Glucuronosyltransferase / Q000378:metabolism; D015227:Lipid Peroxidation; D008862:Microsomes, Liver / Q000187:drug effects*; D015394:Molecular Structure; D009249:NADP; D009281:Naphthalenes / Q000633:toxicity*; D009582:Nitrofurantoin / Q000633:toxicity*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D051381:Rats; D013438:Sulfhydryl Compounds; D000090264:UDP-Glucuronosyltransferase 1A9
D000975:Antioxidants; D004095:Dihydropyridines; D009281:Naphthalenes; D013438:Sulfhydryl Compounds; C031721:naphthalene; D009249:NADP; D009582:Nitrofurantoin; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D001205:Ascorbic Acid