Alterations of Cytochrome P450s and UDP-Glucuronosyltransferases in Brain Under Diseases and Their Clinical Significances

Abstract

Cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs) are both greatly important metabolic enzymes in various tissues, including brain. Although expressions of brain CYPs and UGTs and their contributions to drug disposition are much less than liver, both CYPs and UGTs also mediate metabolism of endogenous substances including dopamine and serotonin as well as some drugs such as morphine in brain, demonstrating their important roles in maintenance of brain homeostasis or pharmacological activity of drugs. Some diseases such as epilepsy, Parkinson’s disease and Alzheimer’s disease are often associated with the alterations of CYPs and UGTs in brain, which may be involved in processes of these diseases via disturbing metabolism of endogenous substances or resisting drugs. This article reviewed the alterations of CYPs and UGTs in brain, the effects on endogenous substances and drugs and their clinical significances. Understanding the roles of CYPs and UGTs in brain provides some new strategies for the treatment of central nervous system diseases.

Transcriptomic evaluation of tau and TDP-43 synergism shows tauopathy predominance and reveals potential modulating targets

“…UGT expression increases following organismal exposure to toxic chemicals ( Meech et al, 2012 ), and are essential for cellular survival under conditions of severe ER stress ( Fanchiotti et al, 1998 ). In the brain, UGTs play a role in metabolism of neurotransmitters such as dopamine and serotonin ( Sheng et al, 2021 ). Activation of the ER unfolded protein response (UPR ER ) has been previously shown to protect against tau neurotoxicity in C. elegans ( Waldherr et al, 2019 ).…”

Exploratory focused pharmacogenetic testing reveals novel markers associated with risperidone pharmacokinetics in Saudi children with autism

“…Collectively, these results highlight the need for further molecular studies to explore the correlation between various UGT genotypes and their induced modifications in UGT enzyme expression in the brain tissues of patients with ASD. This research topic is anticipated to enable a better understanding of altered RIS disposition in the brain and its precise dose individualization requirements under this central nervous system condition ( Sheng et al, 2021 ).…”

“…Recent reviews of ASD genomics using genome-wide association studies (GWASs) revealed considerable overlap between the molecular mechanisms implicated in the etiology of ASD and certain common genes involved in drug absorption, distribution, metabolism, and excretion (ADME) ( Khanzada et al, 2017 ; Sundararajan et al, 2018 ; Fang et al, 2023 ). For example, 11 genes ( SLC6A3 , UGT , GSK3B , HTR2A , MAOA , NOS1AP , PDE4B , TPH2 , CACNA1C , CHRNA7 and DRD2 ) that influence serotonin and dopamine homeostasis and signal transduction pathways affecting mood, behavior and physical activity in ASD are also known to be associated with the pharmacokinetic (PK) and pharmacodynamic (PD) pathways of drugs employed in ASD management ( Butler et al, 2016 ; Sundararajan et al, 2018 ; Sheng et al, 2021 ).…”

CYP2D6genetic polymorphisms in Saudi systemic lupus erythematosus patients

“…of endogenous compounds, such as dopamine and serotonin, to interactions with numerous drugs that are of potential clinical importance for neurological and cognitive disorders. 36,37 Moreover, recent studies showed the association of CYP2D6 * 10 with an increased risk of hepatological and hematological toxicity as a result of drug-related adverse reactions. 38 Interestingly, a recent study investigating the CYP2D6 * 10 in SLE patients showed that the GG genotype had decreased activity.…”