Abstract
UDP-glucuronosyltransferases (UGTs) form a multigenic family of membrane-bound enzymes expressed in various tissues, including brain. They catalyze the formation of β-D-glucuronides from structurally unrelated substances (drugs, other xenobiotics, as well as endogenous compounds) by the linkage of glucuronic acid from the high energy donor, UDP-α-D-glucuronic acid. In brain, UGTs actively participate to the overall protection of the tissue against the intrusion of potentially harmful lipophilic substances that are metabolized as hydrophilic glucuronides. These metabolites are generally inactive, except for important pharmacologically glucuronides such as morphine-6-glucuronide. UGTs are mainly expressed in endothelial cells and astrocytes of the blood brain barrier (BBB). They are also associated to brain interfaces devoid of BBB, such as circumventricular organ, pineal gland, pituitary gland and neuro-olfactory tissues. Beside their key-role as a detoxication barrier, UGTs play a role in the steady-state of endogenous compounds, like steroids or dopamine (DA) that participate to the function of the brain. UGT isoforms of family 1A, 2A, 2B and 3A are expressed in brain tissues to various levels and are known to present distinct but overlapping substrate specificity. The importance of these enzyme species with regard to the formation of toxic, pharmacologically or physiologically relevant glucuronides in the brain will be discussed.
Highlights
They catalyze the formation of β-D-glucuronides from structurally unrelated substances by the linkage of glucuronic acid from the high energy donor, UDP-α-D-glucuronic acid
Beside their key-role as a detoxication barrier, UGTs play a role in the steady-state of endogenous compounds, like steroids or dopamine (DA) that participate to the function of the brain
Beside their significant participation to the overall protection of the brain against the entry of xenobiotics, including pollutants present in our environment, these enzyme species are specialized toward the biotransformation of brain-directed substances, including metabolism of neurotransmitters chemically related to DA, or antipsychotic drugs
Summary
The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication. UGT isoforms of family 1A, 2A, 2B and 3A are expressed in brain tissues to various levels and are known to present distinct but overlapping substrate specificity The importance of these enzyme species with regard to the formation of toxic, pharmacologically or physiologically relevant glucuronides in the brain will be discussed. A LIMITED NUMBER OF UGTs ARE EXPRESSED IN THE BLOOD-BRAIN BARRIER The drug transporters and drug metabolizing enzymes that are present in the BBB prevent access to the brain of some lipid-soluble drugs and potentially toxic substances It has been shown, several years ago, that rat brain microsomes exhibit high glucuronidation activity towards the reference substrate, 1-naphthol (Ghersi-Egea et al, 1987). The construction of an anatomically comprehensive atlas of the adult human brain and mouse transcriptome which is currently under way will undoubtedly bring additional information on the presence of other or novel UGT isoforms (Lein et al, 2007; Sunkin and Hohmann, 2007)
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