The neuroprotective enzyme CYP2D6 increases in the brain with age and is lower in Parkinson's disease patients.

Cytochrome P450 2D6 (CYP2D6) is a drug-metabolizing enzyme expressed in the brain that also metabolizes endogenous neural compounds (e.g., catecholamines) and inactivates neurotoxins (e.g., 1-methyl-4-thenyl-1,2,3,6-tetrahydropyridine; MPTP). Genetically poor CYP2D6 metabolizers are at higher risk for developing Parkinson's disease (PD), a risk that increases with exposure to pesticides. As age is a risk factor for PD we measured the ontogenic expression of CYP2D6 in human brain, and compared brain CYP2D6 levels in PD cases with age-matched controls. CYP2D6 increased from fetal to 80 years of age (n = 76), exhibiting 3 distinct phases of change. Compared with PD controls, PD cases had approximately 40% lower CYP2D6 levels in the frontal cortex, cerebellum, and the hippocampus, even when controlling for CYP2D6 genotype. In contrast, CYP2D6 levels in cases were similar to controls in PD-affected brain areas, the substantia nigra, and caudate, consistent with higher astrocytic and cellular CYP2D6 staining observed in PD cases. In summary, the lower CYP2D6 levels in PD cases may have reduced their ability to inactivate PD-causing neurotoxins contributing to their disease risk.

Rat brain CYP2B induction by nicotine is persistent and does not involve nicotinic acetylcholine receptors.

CYP2B is a drug-metabolizing enzyme expressed in the liver and brain that metabolizes a variety of centrally acting drugs (e.g. propofol, bupropion and nicotine), endogenous neurochemicals (e.g. serotonin and testosterone) and toxins (e.g. chlorpyrifos). Human CYP2B6 is found at higher levels in the brains of smokers, and 7-day nicotine treatment induces rat brain CYP2B while not altering hepatic CYP2B. We characterized the time course of rat brain CYP2B induction by nicotine and determined if nicotinic acetylcholine receptors (nAChRs) mediated this induction. Rats were treated once daily with 1mg/kg nicotine base or saline s.c. for 1 or 7days and sacrificed from 30minutes to 7days after the last injection. One-day nicotine treatment did not induce brain CYP2B, whereas 7-day nicotine treatment significantly increased CYP2B expression for up to 24hours in the frontal cortex and brainstem; these levels returned to baseline by 7days post-treatment. CYP2B activity was also higher at 24hours in these regions. No change was seen in the cerebellar CYP2B levels or in vivo activity following nicotine treatment. Time of day of treatment and sacrifice altered the magnitude of brain CYP2B induction while chlorisondamine, an irreversible nAChR blocker, pre-treatment did not block CYP2B induction. Seven-day nicotine treatment resulted in an induction of rat brain CYP2B protein and in vivo activity for up to 24hours, which would suggest greater local drug metabolism by brain CYP2B. Humans or animals exposed to nicotine may have altered therapeutic drug response, brain levels of neurotransmitters and/or neurotoxicity.

Human CYP2D6 and mouse CYP2Ds: organ distribution in a humanized mouse model.

Polymorphic cytochrome P450 (P450) 2D6 (CYP2D6) metabolizes several classes of therapeutic drugs, endogenous neurochemicals, and toxins. A CYP2D6-humanized transgenic mouse line was previously developed to model CYP2D6-poor and -extensive metabolizer phenotypes. Human CYP2D6 was detected in the liver, kidney, and intestine of these animals. In this study, we investigated further the cellular expression and relative tissue levels of human CYP2D6 in these transgenic mice in liver, intestine, kidney, and brain. In addition, we compared this with the expression of mouse CYP2D enzymes in these organs. In humans, these organs are of interest with respect to P450-mediated drug metabolism, toxicity, and disease. The expression of human CYP2D6 and mouse CYP2D enzymes in humanized and wild-type mice was quantified by immunoblotting and detected at the cellular level by immunocytochemistry. The cell-specific expression of human CYP2D6 in liver, kidney, and intestine in humanized mice was similar to that reported in humans. The expression patterns of mouse CYP2D proteins were similar to those in humans in liver and kidney but substantially different in intestine. Human CYP2D6 was not detected in brain of transgenic mice. Mouse CYP2D proteins were detected in brain, allowing, for the first time, a direct comparison of CYP2D expression among mouse, rat, and human brain. This transgenic mouse model is useful for investigating CYP2D6-mediated metabolism in liver, kidney, and especially the intestine, where expression patterns demonstrated substantial species differences.

Drug-metabolizing cytochrome P450s in the brain.

Most CYP subfamilies have been identified in brain, but there is much more information available on the distribution and metabolic activity of CYP subfamilies in brain of rodents than in humans, and what we do know still lags far behind our knowledge of hepatic CYPs. With the constant acquisition of data on the genetics, molecular structure and metabolic capacity of brain CYPs, we are increasingly able to investigate their role in the brain and the possible consequences of altered local metabolism. However, at this stage, the contribution of brain CYPs to local metabolism of drugs, toxins and endogenous compounds is still speculative, as is the role for these CYPs in modulating brain function and in the development of brain diseases. Much investigative work remains to be done to firmly establish the links between the presence of CYPs in brain, their function in this highly heterogeneous and complex organ and the consequences on overall brain function and health.