Abstract
Cytochrome P450-Mediated Xenobiotic Metabolism in the Brain, Effects of 3,3'-Dichlorobiphenyl (PCB-11) Exposure, and Contributions to Naphthalene-Induced DNA Adducts (Abstract ID: 225165)
The Journal of pharmacology and experimental therapeutics, Vol.393(5 Supplement), 104176
05/2026
DOI: 10.1016/j.jpet.2026.104176
Abstract
The brain is often regarded as being protected from the toxic effects of environmental chemicals and other xenobiotics due to the blood-brain barrier (BBB) and the relatively low expression of xenobiotic-metabolizing enzymes, such as cytochrome P450 (CYP), compared with the liver or other portal-of-entry organs. However, the role of xenobiotic bioactivation in the brain is not well understood. The aim of the present work is to explore the capacity of local xenobiotic bioactivation in the brain, possible enhancement of this capacity by exposures to potential CYP inducers, and the impact of the in situ bioactivation on xenobiotic-induced DNA damage, a potential precursor to neurotoxicity and carcinogenesis. Using bupropion as a probe substrate for CYP2B enzymes in brain microsomal assays, we detected NADPH-dependent formation of OH-bupropion. The microsomal activity was markedly greater in microsomes from mice pretreated with PCB-11, which induced CYP2B10 expression in both liver and the brain, at both protein and mRNA levels. A comparison of wild-type and Cyp2abfgs-null mice showed significantly reduced rates of OH-bupropion formation in the knockout animals, suggesting a predominant contribution of CYP2B10 and possible involvement of additional CYP isoforms in wild-type mice. Brain microsomes were also active toward bioactivation of naphthalene (NA), producing NA-GSH conjugates. The occurrence of NA reactive metabolites in the brain was demonstrated by the detection of NA-DNA adducts, NA-GSH, and naphthoquinone (NQ)-GSH conjugates in the brains of WT mice exposed to NA via inhalation (10 ppm, 4 h) or intraperitoneal injection (200 mg/kg). The ability of circulating NQ to cross the BBB was demonstrated by the detection of NQ-GSH conjugates following NQ administration (intraperitoneal) in wild-type mice. Together, these findings demonstrate that the brain possesses PCB11-inducible, CYP-mediated xenobiotic metabolic capacity, and that reactive NA metabolites in the brain may be formed locally as well as transported from circulation. Further studies are needed to determine whether PCB11 exposure induces brain microsomal metabolism of NA (and/or PCB11), and whether circulating NA metabolites contribute significantly to NA-DNA adduct formation in the brain.
Details
- Title: Subtitle
- Cytochrome P450-Mediated Xenobiotic Metabolism in the Brain, Effects of 3,3'-Dichlorobiphenyl (PCB-11) Exposure, and Contributions to Naphthalene-Induced DNA Adducts (Abstract ID: 225165)
- Creators
- Diksha ManhasWeiguo HanXiangmeng WuSarrah HannonMichelle HollonXueshu LiQing-Yu ZhangHans-Joachim LehmlerLaura Van WinklePamela J. LeinXinxin Ding
- Resource Type
- Abstract
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.393(5 Supplement), 104176
- DOI
- 10.1016/j.jpet.2026.104176
- ISSN
- 0022-3565
- eISSN
- 1521-0103
- Publisher
- Elsevier
- Grant note
- NIH: ES014901, ES020867
Supported in part by NIH grants ES014901 and ES020867.
- Language
- English
- Date published
- 05/2026
- Academic Unit
- Public Health Administration; Occupational and Environmental Health; Iowa Neuroscience Institute
- Record Identifier
- 9985163712402771
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