Cytochrome P450–mediated drug metabolism in the brain

Miksys, Sharon; Tyndale, Rachel F.

doi:10.1503/jpn.120133

Cited by 115 publications

(81 citation statements)

References 156 publications

(211 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Because some DMEs are also found in extrahepatic tissues, including the brain, local brain metabolism could affect the efficacy of central-acting drugs and endogenous compounds, independent of liver metabolism (Dutheil et al, 2008;Miksys and Tyndale, 2013).…”

Section: Introductionmentioning

confidence: 99%

Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain

Sakakibara

Katoh

Kondo

et al. 2015

Drug Metabolism and Disposition

View full text Add to dashboard Cite

UDP-glucuronosyltransferase (UGT), a phase II drug-metabolizing enzyme, is expressed in the brain and can catalyze glucuronidation of endogenous and exogenous substrates in the brain. Thus, changes in UGT1A expression could affect homeostasis and drug efficacy. Phenobarbital (PB), a typical inducer of drug-metabolizing enzymes, has been reported to induce oxidative stress and epigenetic changes, which could alter UGT expression in the brain. Here, we aimed to clarify the effects of PB on Ugt1a6 and Ugt1a7 gene expression in rat brains. Sprague-Dawley rats were treated intraperitoneally with PB (80 mg/kg), once daily for 7 days. Ugt1a6 and Ugt1a7 mRNA expression levels were increased in the striatum and thalamus (Ugt1a6, 3.0-and 2.9-fold, respectively; Ugt1a7, 2.6-and 2.6-fold, respectively). Acetaminophen glucuronidation was also increased in the medulla oblongata and thalamus by 1.8-and 1.2-fold, respectively. The induction rates within different brain regions were correlated with Ugt1a6 and Ugt1a7 mRNA expression, and the degree of induction also correlated with that of NF-E2-related factor-2 mRNA. Measurement of oxidative stress markers suggested that PB induced oxidative stress in brain regions in which Ugt1a6 and Ugt1a7 mRNAs were increased. Moreover, histone modifications were altered by PB treatment, resulting in increased histone H3 lysine 4 trimethylation in the striatum and thalamus and decreased histone H3 lysine 9 trimethylation in the thalamus. These results suggested that oxidative stress and histone modifications may promote transcriptional activation of Ugt1a6 and Ugt1a7 genes. In summary, Ugt1a6 and Ugt1a7 mRNA levels were increased by PB treatment, which may alter pharmacokinetics in the brain.

show abstract

Section: Introductionmentioning

confidence: 99%

Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain

Sakakibara

Katoh

Kondo

et al. 2015

Drug Metabolism and Disposition

View full text Add to dashboard Cite

show abstract

“…This suggests a different pathway for the regulation of liver and brain P450 in CRF. Although significant progress has been made in our understanding of regulation of P450 in the brain and in different regions of the brain (Meyer et al, 2007;Miksys and Tyndale, 2013), our data indicate a possible different mode of P450 regulation in the brain compared with the liver. Our results point toward post-translational regulation, but the exact mechanisms involved remains to be identified.…”

Section: Discussionmentioning

confidence: 58%

“…Brain P450s are involved in the metabolism of xenobiotics, such as antidepressants, opiates, steroids, and antipsychotics, as well as endobiotics, such as steroids, arachidonic acid, dopamine, and serotonin (Miksys and Tyndale, 2013). P450 isoforms such as CYP1A1/2, CYP2B1, CYP2C11, CYP2D1-6, CYP2E1, CYP3A1, and CYP4F have been identified in rat brain (Morse et al, 1998;Imaoka et al, 2005;Yadav et al, 2006;Miksys and Tyndale, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…P450 isoforms such as CYP1A1/2, CYP2B1, CYP2C11, CYP2D1-6, CYP2E1, CYP3A1, and CYP4F have been identified in rat brain (Morse et al, 1998;Imaoka et al, 2005;Yadav et al, 2006;Miksys and Tyndale, 2013). Although the overall expression of individual P450s in the brain is low, high activity of specific P450 enzymes can be found in different brain regions, such as the hippocampus, cerebellum, cortex, and hypothalamus, where these proteins are suggested to participate in local endobiotic and xenobiotic metabolism (Miksys and Tyndale, 2002;Yadav et al, 2006;Meyer et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of Chronic Renal Failure on Brain Cytochrome P450 in Rats

Naud

Harding

Lamarche

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

Chronic renal failure (CRF) impedes renal excretion of drugs and their metabolism by reducing the expression of liver cytochrome P450 (P450). Uremic serum contains factors, such as parathyroid hormone (PTH), that decrease liver P450s. The P450s are also involved in the metabolism of xenobiotics in the brain. This study investigates: 1) the effects of CRF on rat brain P450, 2) the role of PTH in the downregulation of brain P450s in CRF rats, and 3) the effects of PTH on P450s in astrocytes. Protein and mRNA expression of P450s were assessed in the brain of CRF and control (CTL) rats, as well as from CTL or CRF rats that underwent parathyroidectomy (PTX) 1 week before nephrectomy. CYP3A activity was measured using 3-[(3, 4-difluorobenzyl) oxy]-5, 5-dimethyl-4-[4-methylsulfonyl) phenyl] furan-2(5H)-1 metabolism in brain microsomal preparation.CYP3A protein expression was assessed in primary cultured astrocytes incubated with serum obtained from CRF or CTL rats or with PTH. Significant downregulations ( ‡40%) of CYP1A, CYP2C11, and CYP3A proteins were observed in microsomes from CRF rat brains. CYP3A activity reduction was also observed. CYP3A expression and activity were unaffected in PTX-pretreated CRF rats. Serum of PTX-treated CRF rats had no impact on CYP3A levels in astrocytes compared with that of untreated CRF rats. Finally, PTH addition to normal calf serum induced a reduction in CYP3A protein similar to CRF serum, suggesting that CRF-induced hyperparathyroidism is associated with a significant decrease in P450 drugmetabolizing enzymes in the brain, which may have implications in drug response.

show abstract

“…27,28 CYP P450 enzymes are known to be present not only in peripheral organs, but also in the brain, where they may modulate local levels of endogenous and exogenous psychoactive compounds in a region-specific manner. 29 For example, in various brain regions, smokers have higher levels of CYP2B6, an enzyme capable of metabolizing endogenous compounds, such as serotonin and testosterone, as well as exo genous agents, such as nicotine, cocaine, amphetamines and buproprion. 30 Therefore, in a number of instances, the effects of smoking status on metabolism of psychoactive drugs may be an additional way in which smoking could influence meas ures of brain function in some psychiatric populations.…”

Section: Smoking As a Modulator Of Effects Of Psychotropic Medicationsmentioning

confidence: 99%

Smoking, psychiatric illness and the brain

Boksa

2017

JPN

View full text Add to dashboard Cite

Tobacco smoking remains a leading cause of mortality and morbidity despite recent declines in prevalence. In 2012, global prevalence rates for tobacco smoking were estimated to be 31% for men and 6% for women.1 Rates of smoking are markedly higher among people with psychiatric illness than in the general population, estimated at being 2-5 times higher in patients with several disorders, including schizophrenia, mood disorders, anxiety disorders, attentiondeficit/hyperactivity disorder (ADHD), binge eating disorder, bulimia and substance use disorders. 2-5

show abstract

Cytochrome P450–mediated drug metabolism in the brain

Cited by 115 publications

References 156 publications

Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain

Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain

Effects of Chronic Renal Failure on Brain Cytochrome P450 in Rats

Smoking, psychiatric illness and the brain

Contact Info

Product

Resources

About