Drug and xenobiotic biotransformation in the blood–brain barrier: a neglected issue

Abstract

Drug biotransformation is a crucial mechanism for facilitating the elimination of chemicals from the organism and for decreasing their pharmacological activity. Published evidence suggests that brain drug metabolism may play a role in the development of adverse drug reactions and in the clinical response to drugs and xenobiotics. The blood–brain barrier (BBB) has been regarded mainly as a physical barrier for drugs and xenobiotics, and little attention has been paid to the BBB as a drug-metabolizing barrier. The presence of drug-metabolizing enzymes in the BBB is likely to have functional implications because local metabolism may inactivate drugs or may modify the drug’s ability to cross the BBB, thus modifying drug response and the risk of developing adverse drug reactions. In this perspective paper, we discuss the expression of relevant xenobiotic metabolizing enzymes in the brain and in the BBB, and we cover current advances and future directions on the potential role of these BBB drug-metabolizing enzymes as modifiers of drug response.

Review: The blood-brain barrier; protecting the developing fetal brain

“…Drug metabolising enzymes at the BBB and placenta may significantly affect drug transfer through these barriers, and biotransformation by these enzymes may affect movement of substances by barrier efflux transporters [72,73]. Drug metabolising enzymes with actions at the BBB include phase I and phase II enzymes such as cytochrome P450 and glutathione S-transferases [74]. In addition, there are other routes into the brain other than the BBB, these include the blood-CSF barrier between the systemic blood supply and the choroid plexus, the meningeal barrier, and the fetal-specific CSF-brain barrier [11].…”

The Role of CYP2E1 in the Drug Metabolism or Bioactivation in the Brain

“…CYP1B1 and CYP2U1 are expressed twice as much in the brain than in the liver. The expression of CYP1A, CYP2C8, CYP2C19, CYP3A4, CYP3A5, and CYP2E1 seems to be negligible in the human brain [22]. …”

“…CYP1B1 has been identified in microvessels and has an emphasized role of quantitative importance in the brain blood barrier (BBB) [23]. CYP1B1 and CYP2U1 transcripts were mainly detected in brain microvessels, whereas no other CYP proteins were detected [22]. BBB expressed different CYP450 isoforms in high levels, forming a metabolic barrier, regulating the blood flow, compound flow, and signal during inflammation.…”

The Microbiota–Gut–Brain Axis Heart Shunt Part I: The French Paradox, Heart Disease and the Microbiota

“…This may also help protect the French from lipid peroxidation and heart disease [50]. Moreover, xenobiotic molecules could affect the CNS and brain at both the blood-brain-barrier interface [51] and from gut dysbiosis, which could be a cause and a consequence of increased levels of oxidative stress since anaerobes thrive in the presence of electron acceptors [52]. A reaction that is well-quenched by many polyphenols is the Fenton reaction, which involves hydroxyl radicals.…”