Reactive oxygen species and non-peroxidative mechanisms of cocaine-induced cytotoxicity in rat hepatocyte cultures

Total antioxidant capacity is significantly lower in cocaine‐dependent and methamphetamine‐dependent patients relative to normal controls: results from a preliminary study

“…Our results are in accordance with previous results in mice, treated with 20 mg/kg body weight cocaine, which showed reduced activities of CAT and GSH‐Px compared with the control mice (Labib et al , ). The authors concluded that the ROS generated by cocaine metabolites (Goldlin and Boelsterli, ; Boelsterli et al , ) lead to a decrease of enzyme activities of GSH‐Px and CAT compared with the saline control (Labib et al ., ). In the animal studies on oxidative damage caused by cocaine (Labib et al ., ; Muriach et al , ), the SOD, CAT, or GSH‐Px activities were measured in the target tissues, liver and brain, but not in the blood.…”

Total antioxidant capacity is significantly lower in cocaine‐dependent and methamphetamine‐dependent patients relative to normal controls: results from a preliminary study

“…Our results are in accordance with previous results in mice, treated with 20 mg/kg body weight cocaine, which showed reduced activities of CAT and GSH‐Px compared with the control mice (Labib et al , ). The authors concluded that the ROS generated by cocaine metabolites (Goldlin and Boelsterli, ; Boelsterli et al , ) lead to a decrease of enzyme activities of GSH‐Px and CAT compared with the saline control (Labib et al ., ). In the animal studies on oxidative damage caused by cocaine (Labib et al ., ; Muriach et al , ), the SOD, CAT, or GSH‐Px activities were measured in the target tissues, liver and brain, but not in the blood.…”

Extrapolating In vitro Metabolic Interactions to Isolated Perfused Liver: Predictions of Metabolic Interactions between R-Bufuralol, Bunitrolol, and Debrisoquine

“…Such variability can arise in the cytochrome P450 isoenzyme concentrations, the relative proportion of each isoenzyme and in the affinity of the drugs to the enzymes involved. Although variability of these factors was shown to be of great importance in humans, 48 it remains to be verified whether it has any significance in rats of the same strain. PBPK models offer the possibility to incorporate interindividual variability of the factors affecting hepatic clearance and metabolic DDIs in order to predict the possible range of these processes for speculative purposes.…”

Oxygen free radical production mediated by cocaine and its ethanol-derived metabolite, cocaethylene, in rat hepatocytes

“…We also investigated whether the two drug congeners share a common molecular mechanism of cell injury. Indirect evidence has been accumulating to show that cocaine hepatotoxicity is related to oxidative damage in hepatocytes, possibly involving mitochondria1 injury (12,19,25). Therefore we measured the production of ROS during the microsomal metabolism of the compounds.…”

“…Earlier evidence for a role of cocaine-induced oxidative stress that could play a role in the killing of cultured hepatocytes stemmed from indirect observations. For example, the protection against cocaine-mediated cell injury afforded by the iron chelator dcferoxamine but not by the antioxidant TPGA (a-tocopherol polyethylene glycol 1,000 succinate) was indicative of a causative role of iron-dependent oxidative mechanisms in rat hepatocytes, independent of lipid peroxidation (19). Furthermore, cocaine-mediated oxidized glutathione formation in mouse liver (25) and in cultured rat hepatocytes (Goldlin and Boelsterli, Unpublished data, 1993) suggests that oxidative stress plays a role in cocaine bioactivation and toxicity.…”

Total antioxidant capacity is significantly lower in cocaine‐dependent and methamphetamine‐dependent patients relative to normal controls: results from a preliminary study

“…Our results are in accordance with previous results in mice, treated with 20 mg/kg body weight cocaine, which showed reduced activities of CAT and GSH‐Px compared with the control mice (Labib et al , ). The authors concluded that the ROS generated by cocaine metabolites (Goldlin and Boelsterli, ; Boelsterli et al , ) lead to a decrease of enzyme activities of GSH‐Px and CAT compared with the saline control (Labib et al ., ). In the animal studies on oxidative damage caused by cocaine (Labib et al ., ; Muriach et al , ), the SOD, CAT, or GSH‐Px activities were measured in the target tissues, liver and brain, but not in the blood.…”

Extrapolating In vitro Metabolic Interactions to Isolated Perfused Liver: Predictions of Metabolic Interactions between R-Bufuralol, Bunitrolol, and Debrisoquine

“…Such variability can arise in the cytochrome P450 isoenzyme concentrations, the relative proportion of each isoenzyme and in the affinity of the drugs to the enzymes involved. Although variability of these factors was shown to be of great importance in humans, 48 it remains to be verified whether it has any significance in rats of the same strain. PBPK models offer the possibility to incorporate interindividual variability of the factors affecting hepatic clearance and metabolic DDIs in order to predict the possible range of these processes for speculative purposes.…”

Oxygen free radical production mediated by cocaine and its ethanol-derived metabolite, cocaethylene, in rat hepatocytes

“…We also investigated whether the two drug congeners share a common molecular mechanism of cell injury. Indirect evidence has been accumulating to show that cocaine hepatotoxicity is related to oxidative damage in hepatocytes, possibly involving mitochondria1 injury (12,19,25). Therefore we measured the production of ROS during the microsomal metabolism of the compounds.…”

“…Earlier evidence for a role of cocaine-induced oxidative stress that could play a role in the killing of cultured hepatocytes stemmed from indirect observations. For example, the protection against cocaine-mediated cell injury afforded by the iron chelator dcferoxamine but not by the antioxidant TPGA (a-tocopherol polyethylene glycol 1,000 succinate) was indicative of a causative role of iron-dependent oxidative mechanisms in rat hepatocytes, independent of lipid peroxidation (19). Furthermore, cocaine-mediated oxidized glutathione formation in mouse liver (25) and in cultured rat hepatocytes (Goldlin and Boelsterli, Unpublished data, 1993) suggests that oxidative stress plays a role in cocaine bioactivation and toxicity.…”

Total antioxidant capacity is significantly lower in cocaine‐dependent and methamphetamine‐dependent patients relative to normal controls: results from a preliminary study

“…Our results are in accordance with previous results in mice, treated with 20 mg/kg body weight cocaine, which showed reduced activities of CAT and GSH‐Px compared with the control mice (Labib et al , ). The authors concluded that the ROS generated by cocaine metabolites (Goldlin and Boelsterli, ; Boelsterli et al , ) lead to a decrease of enzyme activities of GSH‐Px and CAT compared with the saline control (Labib et al ., ). In the animal studies on oxidative damage caused by cocaine (Labib et al ., ; Muriach et al , ), the SOD, CAT, or GSH‐Px activities were measured in the target tissues, liver and brain, but not in the blood.…”

Extrapolating In vitro Metabolic Interactions to Isolated Perfused Liver: Predictions of Metabolic Interactions between R-Bufuralol, Bunitrolol, and Debrisoquine

“…Such variability can arise in the cytochrome P450 isoenzyme concentrations, the relative proportion of each isoenzyme and in the affinity of the drugs to the enzymes involved. Although variability of these factors was shown to be of great importance in humans, 48 it remains to be verified whether it has any significance in rats of the same strain. PBPK models offer the possibility to incorporate interindividual variability of the factors affecting hepatic clearance and metabolic DDIs in order to predict the possible range of these processes for speculative purposes.…”

Oxygen free radical production mediated by cocaine and its ethanol-derived metabolite, cocaethylene, in rat hepatocytes

“…We also investigated whether the two drug congeners share a common molecular mechanism of cell injury. Indirect evidence has been accumulating to show that cocaine hepatotoxicity is related to oxidative damage in hepatocytes, possibly involving mitochondria1 injury (12,19,25). Therefore we measured the production of ROS during the microsomal metabolism of the compounds.…”

“…Earlier evidence for a role of cocaine-induced oxidative stress that could play a role in the killing of cultured hepatocytes stemmed from indirect observations. For example, the protection against cocaine-mediated cell injury afforded by the iron chelator dcferoxamine but not by the antioxidant TPGA (a-tocopherol polyethylene glycol 1,000 succinate) was indicative of a causative role of iron-dependent oxidative mechanisms in rat hepatocytes, independent of lipid peroxidation (19). Furthermore, cocaine-mediated oxidized glutathione formation in mouse liver (25) and in cultured rat hepatocytes (Goldlin and Boelsterli, Unpublished data, 1993) suggests that oxidative stress plays a role in cocaine bioactivation and toxicity.…”