Independent and combined effects of ethanol self-administration and nicotine treatment on hepatic CYP2E1 in African green monkeys.
ABSTRACT Cytochrome P450 2E1 metabolizes ethanol and also bioactivates many toxins and procarcinogens. Elevated levels of hepatic CYP2E1 are associated with an increased susceptibility to chemical toxicity and carcinogenesis. This study investigated the induction of hepatic CYP2E1 by ethanol and nicotine, alone and in combination, in a nonhuman primate model. Monkeys that self-administered ethanol and that received subcutaneous injections of nicotine (0.5 mg/kg b.i.d.), alone and in combination, were compared with control animals (four groups, n = 10/group). Chlorzoxazone (CZN) was used as a probe drug to phenotype in vivo CYP2E1 activity before and after chronic ethanol and/or nicotine exposure. CYP2E1 protein levels and in vitro chlorzoxazone metabolism were assessed in liver microsomes. Average daily ethanol consumption was ≈3.0 g/kg (blood ethanol levels ≈24 mM) and was unaffected by nicotine treatment. Ethanol self-administration and nicotine treatment, alone and in combination, significantly increased in vivo CZN disposition compared with that in control animals. The effect of ethanol was only observed at higher levels of intake. Ethanol and nicotine increased CYP2E1 protein levels and in vitro CZN metabolism, with combined exposure to both drugs resulting in the greatest increase. The effect of ethanol was also dependent on level of intake. Chronic exposure to ethanol and nicotine induced hepatic CYP2E1 activity and protein levels, particularly when both drugs were used in combination and when ethanol intake was high. These results have important implications for public health, given the association between elevated CYP2E1 and disease, and the large proportion of individuals who are exposed to ethanol and nicotine, often in combination.
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ABSTRACT: CYP2D6 metabolizes many centrally acting drugs, neurotoxins, and endogenous neurochemicals and differences in brain levels of CYP2D have been associated with brain function and drug response. Alcohol consumers and smokers have higher levels of CYP2D6 in brain, but not liver, suggesting ethanol and/or nicotine may induce human brain CYP2D6. We investigated the independent and combined effects of chronic ethanol self-administration and nicotine treatment on CYP2D expression in African green monkeys. Forty monkeys were randomized into control, ethanol-only, nicotine-only, and ethanol+nicotine groups. Two groups voluntarily self-administered 10% ethanol in sucrose solution for 4 hours/day, while two groups consumed sucrose solution on the same schedule. Two groups received daily subcutaneous injections of 0.5 mg/kg nicotine in saline bid, while two groups were injected with saline on the same schedule. Both nicotine and ethanol dose-dependently increased CYP2D in brain; brain mRNA was unaffected, and neither drug altered hepatic CYP2D protein or mRNA. The combination of ethanol and nicotine induced brain CYP2D protein levels to a greater extent than either drug alone (1.2-2.2 fold, p < 0.05 among the eight brain regions assessed). Immunohistochemistry revealed induction of brain CYP2D protein within specific cell types and regions in the treatment groups. Ethanol and nicotine increase brain CYP2D protein levels in monkeys, in a region and treatment specific manner, suggesting that CNS drug response, neurodegeneration, and personality may be affected among people who consume alcohol and/or nicotine.British Journal of Pharmacology 02/2014; · 5.07 Impact Factor
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ABSTRACT: In several animal species including humans, the acute administration of low doses of alcohol increases motor activity. Different theories have postulated that alcohol-induced hyperactivity is causally related to alcoholism. Moreover, a common biological mechanism in the mesolimbic dopamine system has been proposed to mediate the stimulant and motivational effects of alcohol. Numerous studies have examined whether alcohol-induced hyperactivity is related to alcoholism using a great variety of animal models and several animal species. However, there is no review that has summarized this extensive literature. In this article, we present the various experimental models that have been used to study the relationship between the stimulant and motivational effects of alcohol in rodents and primates. Furthermore, we discuss whether the theories hypothesizing a causal link between alcohol-induced hyperactivity and alcoholism are supported by published results. The reviewed findings indicate that animal species that are stimulated by alcohol also exhibit alcohol preference. Additionally, the role of dopamine in alcohol-induced hyperactivity is well established since blocking dopaminergic activity suppresses the stimulant effects of alcohol. However, dopamine transmission plays a much more complex function in the motivational properties of alcohol and the neuronal mechanisms involved in alcohol stimulation and reward are distinct. Overall, the current review provides mixed support for theories suggesting that the stimulant effects of alcohol are related to alcoholism and highlights the importance of animal models as a way to gain insight into alcoholism.Pharmacology Biochemistry and Behavior 01/2014; · 2.82 Impact Factor
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ABSTRACT: CYP2B6 and CYP2E1 are enzymes responsible for the metabolism of many centrally acting drugs, toxins and endogenous compounds. Human smokers and alcoholics have elevated levels of CYP2B6 and CYP2E1 in certain brain regions, which may contribute to altered drug efficacy, neurotoxicity and metabolic tolerance. The objective of this study was to determine the effects of ethanol self-administration and nicotine treatment, alone and in combination, on brain CYP2B6 and CYP2E1 levels in monkeys. Monkeys were randomized into four groups (N=10/group): an ethanol-only group, a nicotine-only group, an ethanol + nicotine group and a control (no drug) group. Ethanol (10% alcohol in sucrose solution) was voluntarily self-administered by the monkeys and nicotine was given as subcutaneous injections (0.5 mg/kg bid). Immunocytochemistry revealed induction of both CYP2B6 and CYP2E1 protein in certain brain regions and cells within monkey brain as a result of ethanol self-administration, nicotine treatment and combined exposure to both drugs. Immunoblotting analyses demonstrated CYP2B6 induction by ethanol in the caudate, putamen and cerebellum (1.5-3.2 fold, P<0.05), and CYP2E1 induction by nicotine in the frontal cortex and putamen (1.6-2.0 fold, P<0.05). Combined ethanol and nicotine exposure induced CYP2B6 in the caudate, putamen, thalamus and cerebellum (1.4-2.4 fold, P<0.05), and CYP2E1 in the frontal cortex and putamen (1.5-1.8, P<0.05). CYP2B6 and CYP2E1 mRNA levels were unaffected by ethanol or nicotine exposure. In summary, ethanol and nicotine can induce CYP2B6 and CYP2E1 protein in the primate brain, which could potentially result in altered sensitivity to centrally acting drugs and toxins.Neuropharmacology 04/2013; · 4.11 Impact Factor