Cytochrome P450 (CYPs) enzymes are responsible for the metabolism of many exogenous and endogenous compounds. CYPs are abundant in the liver and are also expressed in many extra-hepatic tissues including the brain. Although the total CYP levels in the brain are much lower than in the liver, brain CYPs are concentrated near drug targets in specific regions and cell types, potentially having a considerable impact on local metabolism. Individual differences in brain CYP metabolism, due to inducers, inhibitors or genetic variation, can influence sensitivity and response to centrally acting drugs. Brain CYPs may also play a role in modulating brain activity, behavior, susceptibility to CNS diseases and treatment outcomes. This review highlights the recent progress that has been made in understanding the functional significance of CYPs in the brain.

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 selfadministered 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 Ϸ3.0 g/kg (blood ethanol levels Ϸ24 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.

Drug dependency is a highly prevalent mental health disorder that imposes a significant burden on those directly affected, health care systems, and society in general. There is substantial heritability in the susceptibility to drug addiction, which indicates that there are genetic risk factors. Variation in the human genome is abundant and can directly affect drug dependency phenotypes, for example, by altering the function of a gene product or by altering gene expression. Pharmacogenetic studies can assess the effects of genetic variation on the risk for a particular phenotype (e.g., being an alcoholic). In addition, pharmacogenetic variability in treatment efficacy and adverse reactions can be investigated to identify particular genetic variants associated with altered responses. This review highlights examples of genetic variations that are important in the development and maintenance of specific drug dependencies as well as those that affect the response to treatment.