Pharmacological and toxicological significance of brain cytochromes P450.

Abstract

Metabolism of foreign compounds in the body to polar, hydrophilic metabolites is important for detoxification and elimination of the xenobiotic from the body. A major enzyme system involved in the metabolism of foreign compounds is cytochrome P-450 (P-450) and associated monooxygenases. Multiple forms of P-450 which are selectively induced or inhibited by a variety of drugs and xenobiotics are known to exist in liver, the major organ involved in P-450 mediated metabolism [Ortiz de Montellano, 1986]. However, the importance of extrahepatic metabolism has been increasingly recognized, especially with respect to its potential role in target organ toxicity, and has prompted investigation into the xenobiotic metabolizing capability of extrahepatic organs such as kidney, lung, olfactory epithelium, etc. [Gram et al, 1986]. These studies have revealed the preferential localization of drug metabolizing enzymes within specific cell types in these organs rendering them vulnerable to damage by bioactivation, in situ within these cells. Brain, particularly the human brain is one of the most complex organs both functionally and anatomically. It exhibits a multitude of diversity both with respect to its distinct anatomical regions and cellular elements. Brain comprises of anatomically distinct entities, each with its specialized function, which are interconnected through complex neural networks for effective communication. It is highly vulnerable to damage by toxic compounds, due to limited regenerative capability of the neurons, the major cell type involved in neurotransmission and other specialized functions of the brain. The distinctive features of the capillary endothelial cells surrounding the cerebral blood vessels render protection to the brain by preventing the entry of circulating molecules. The blood-brain barrier, as this hypothetical barrier is commonly known, results from the presence of tight junctions and the lack of pinocytic vesicles. However, xenobiotics which are lipophilic in character can diffuse through the endothelial cells of the brain capillaries and enter the neuronal cells. Thus, bioactivation in situ in the neuronal cell can have far-reaching consequences by causing irreversible disruption of neuronal function. A role for environmental toxins in the etiopathogenesis of