Sex and strain differences in response to cocaine
Abstract
After pretreatment with phenobarbital, female B6AF1 mice showed considerably higher serum glutamic oxaloacetic transaminase (SGOT) elevations and more periportal necrosis from a single injection of cocaine than males. This sex difference was androgen dependent. Castration or treatment with flutamide made males respond like females, while testosterone made females behave like males. There was no significant sex difference in enzymes of cocaine metabolism. When the mice were induced by exposure to pine bedding, males showed higher SGOT elevations and more centrilobular necrosis after cocaine than females. In this case, the sex difference could be attributed to increased levels of cytochrome P-450 and cocaine N-demethylase in liver microsomes. BALB/cBy mice on pine bedding snowed much less liver damage from cocaine than B6AF1 mice, but they were more sensitive to norcocaine and N-hydroxy norcocaine. This difference was correlated with low levels of cocaine N-demethylase in the BALB/cBy mice. Liver microsomes from phenobarbital-induced BALB/cBy mice had less norcocaine N-hydroxylase activity than those from B6AF1 mice. These studies demonstrate that the pattern of sex and strain differences in liver damage from cocaine depends on the inducing agent and can be related to a large extent to the microsomal enzymes induced by that agent.
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Effect of ketamine pretreatment on cocaine-mediated hepatotoxicity in rats
2004, Toxicology LettersCocaine (COC) produces hepatotoxicity by a mechanism, which remains undefined, but has been linked to its oxidative metabolism. Ketamine (KET) is also a potentially hepatotoxic agent. The abuse of KET with COC is currently popular among young abusers therefore; this study was conducted to investigate the possible potentiation of COC-mediated hepatotoxicity (CMH) by KET. Male Sprague Dawley (SD) rats were administered oral KET hydrochloride for three consecutive days at a dose of 100 mg/kg with and without a single dose of COC (5 mg/kg, i.v.) administered 18 h after the last KET dose. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured as markers of liver injury. Liver reduced glutathione (GSH) levels were determined as well as the activities of glutathione peroxidase (GPx) and catalase (CAT). In addition, the activity of liver glutathione reductase (GRx) was measured.
The results demonstrate that KET pretreatment potentiated the hepatotoxicity of COC. Serum ALT and AST were significantly elevated with the combined KET and COC treatment versus all other treatments. While COC alone resulted in focal inflammatory cell infiltration, COC administration after KET pretreatment produced sub-massive hepatic necrosis. Hepatic GSH content was significantly reduced in KET-pretreated COC group compared to the other treatment groups, rendering the liver more susceptible to oxidative stress. Moreover, there was a significant decrease in the activities of hepatic GPx and CAT, particularly with the KET-pretreated COC group. In addition, norcocaine (NC) was only detected in the plasma of rats received COC after KET pretreatment.
In conclusion, this study demonstrates that KET pretreatment potentiates the hepatotoxicity of COC as revealed by an array of biochemical and morphological markers most probably due to increase in COC oxidative metabolism.
Oral cocaine produces dose-related hepatotoxicity in male mice
2001, Toxicology LettersCocaine remains a widely abused substance. While most addicts take cocaine intranasally, a considerable number abuse cocaine by mouth. It has been assumed that after oral exposure cocaine is hydrolyzed in the stomach rendering it ineffective. This study investigated the effect of orally administered cocaine on liver function and integrity as well as its effect on liver and blood antioxidative enzymes. Male CF-1 mice were orally administered either 0, 5, 10 or 20 mg cocaine/kg body weight and sacrificed 24 h after the last treatment. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured as markers of liver injury. Blood and liver glutathione (GSH) levels were determined as well as the activities of glutathione peroxidase (GPx) and catalase (CAT). In addition, the activity of liver glutathione reductase (GRx) was also measured. The results demonstrated that oral cocaine caused hepatotoxicity in a dose dependent manner. Serum ALT and AST were elevated while blood GSH concentration decreased in all cocaine treated animals. In addition, there was a significant dose dependent decrease in the activities of GPx and CAT in blood and liver of cocaine treated animals. However, hepatic GSH content and GRx activity manifested a significant increase, particularly in the group, which received 20 mg/kg cocaine. This study is the first to demonstrate that cocaine-induced hepatotoxicity results following the oral route of administration.
The effects of phencyclidine pretreatment on cocaine-mediated hepatotoxicity in mice
2001, Toxicology and Applied PharmacologyCocaine-mediated hepatotoxicity (CMH) requires cocaine (CCN) bioactivation by microsomal monooxygenase enzymes that results in cell death. Proposed mechanisms of toxicity involve reactive metabolites that covalently bind to hepatocellular proteins, depletion of cellular reducing equivalents through redox cycling, and/or the generation of reactive oxygen and nitrogen species that alter lipids and proteins. We have previously shown that phencyclidine (PCP) pretreatment potentiated CMH in CF-1 mice without increasing in vitro N-demethylation or N-hydroxylation of CCN. We have now further characterized PCP-potentiated CMH and determined that it is a dose- and time-dependent process, with PCP doses as low as 2.5 mg/kg for 3 days significantly increasing CMH. Immunohistochemistry and histology of livers from mice pretreated with PCP before CCN administration revealed a marked correlation between the regions of CCN metabolite binding and that of necrosis, whereas there was little binding or necrosis in vehicle-pretreated mice. Although hepatic GSH levels were not altered after repetitive PCP treatment alone, a sustained decrease (at least 6 h) in these levels was observed following CCN administration. Inhibitors of inducible nitric oxide synthase (NOS) abrogated PCP-potentiated CMH, although repetitive PCP treatment alone did not increase nitric oxide synthesis systemically or locally in hepatic tissue nor did lipopolysaccharide induction of NOS (without PCP) directly potentiate CMH. The precise mechanisms of PCP potentiation of CMH and involvement of NOS in CMH remain unclear, however, sustained depletion of GSH levels and increased hepatocellular binding of reactive cocaine metabolites have been demonstrated.
Pretreatment of male BALB/c mice with β-ionone potentiates thioacetamide-induced hepatotoxicity
1999, Toxicology LettersA possible role of metabolic activation by cytochrome P450 (P450) in thioacetamide-induced hepatotoxicity was investigated in male BALB/c mice. The mice were pretreated with the P450 inducer, β-ionone, subcutaneously at 600 mg/kg, 72 and 48 h prior to an intraperitoneal administration of either 100 or 200 mg/kg of thioacetamide. The elevated activities of serum alanine aminotransferase and serum aspartate aminotransferase by thioacetamide were greatly potentiated by the pretreatment with β-ionone. Moreover, the potentiation of thioacetamide-induced hepatotoxicity was also observed in the histopathological examination of livers. The hepatic necrosis by thioacetamide was potentiated when mice were pretreated with β-ionone. In liver microsomes, the activities of P450 2B-specific pentoxyresorufin O-depentylase and benzyloxyresorufin O-debenzylase were significantly induced by the treatment with β-ionone. β-Ionone also induced other P450-associated monooxygenases. Because the pretreatment with β-ionone was not hepatotoxic at the dose inducing P450s, our present results suggest that β-ionone may be a useful model inducer of P450 enzyme(s) in studying toxic mechanism of certain chemicals which require metabolic activation by P450s in mice.
Effects of β-ionone on the expression of cytochrome P450s and NADPH-cytochrome P450 reductase in Sprague Dawley rats
1998, Chemico-Biological InteractionsWe have recently reported that β-ionone induces cytochrome P450 (P450) 2B1 in rats. Effects of β-ionone on the expression of other P450 isozymes and NADPH-P450 reductase were further investigated in Sprague Dawley rats. Administration of β-ionone subcutaneously 72 and 48 h before sacrificing the animals not only significantly induced the liver microsomal activities of P450-associated enzymes and NADPH-P450 reductase, but also clearly increased in the level of P450 1A1/2, P450 2C, and NADPH-P450 reductase proteins. The induction of P450 1A1/2 and 2C by β-ionone was much greater in male than in female as measured by western immunoblotting. Reverse transcriptase-polymerase chain reactions showed that, in addition to P450 2B1 and 2B2 mRNAs, P450 1A2, 2C6 and NADPH-P450 reductase mRNAs were increased when β-ionone was administered. Our previous and present results indicated that β-ionone may induce several P450s and NADPH-P450 reductase by the accumulation of their corresponding mRNAs.
Membrane potential of hepatic mitochondria after acute cocaine administration in rats - The role of mitochondrial reduced glutathione
1997, HepatologyCocaine hepatotoxicity may be mediated by oxidative damage, possibly involving mitochondrial injury. The effect of an acute dose of cocaine in rats on the mitochondrial level of reduced glutathione, nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), important determinants in cellular defense against oxidative stress, was investigated. Under these conditions, the extent of lipid peroxidation was assessed as thiobarbituric acid reactive substances formation and the energy transducing capability of the inner mitochondrial membrane was evaluated by membrane potential measurements. Female Wistar albino rats were given an acute 50 mg/kg intraperitoneal dose of cocaine and, 6 hours later, hepatic and mitochondrial biochemical analyses were made. Rats administered intraperitoneally, 7.5 hours before the sacrifice, a specific inhibitor of glutathione synthesis, L-buthionine-(S,R)-sulphoximine, either alone or in combination with cocaine, underwent in parallel the same determinations. Cocaine intoxication did not impair mitochondrial functions, although a significant increase of lipid peroxidation occurred. By contrast the combination of L-buthionine-(S,R)-sulphoximine with cocaine induced a severe derangement of mitochondrial functional efficiency, a large depletion of reduced glutathione, and a further enhancement of lipid peroxidation. The mitochondrial functional anomalies were largely restored by the use of cyclosporin A, ethyleneglycotetraacetic acid (EGTA) and glutathione methylmonoester. A nonspecific calcium dependent inner membrane permeabilty transition (pore opening) accounted for the partial loss of mitochondrial coupled functions at a period of cocaine intoxication when no cell damage occurred. The level of mitochondrial glutathione played a critical role in protecting inner membrane functional integrity against cocaine-induced oxidative stress.
(Hepatology 1997 Feb;25(2):385-90)