Mitchell, Stephen Charles (1986). THE METABOLISM AND TOXICITY OF PHENOTHIAZINE. BPhil thesis The Open University.



Phenothiazine, first prepared in 1883 during research into aniline dyestuffs , is the parent molecule of a multitude of drugs which have found varied and extensive use in clinical practice. The compound itself possesses insecticidal, antibacterial, antifungal and anthelmintic properties . Its major use has been as a vermifuge which enabled the provision of many tons of infection-free food and sheep intestine (catgut) which were desperately required during World War II . For this reason alone phenothiazine deserves recognition alongside penicillin and DDT for its remarkable effect on mankind.

To be effective as an anthelmintic the compound has to be given in large doses and because of its high lipid solubility becomes widely distributed around the body. Here it undergoes enzymatically catalysed chemical alterations, mainly oxidations of the carbon and sulphur atoms and conjugation reactions with glucuronic and sulphuric acids. The therapeutic actions of phenothiazine and the production of its unwanted toxic effects (haemolytic, neuromuscular, photosensitization) presumably arise from common underlying mechanisms, the toxic effects perhaps being aggravated by an environmental or genetic predisposition. Three basic ways in which the phenothiazine molecule interacts with the cellular components of tissues to produce these observed effects have become apparent from evaluating the available literature. These are the non-specific macromolecular disruptions that can occur to lipid or protein molecules in membranes and other locations, the formation of metabolite redox systems to permit energy transfer to disrupt cellular components and enzyme systems and the formation of allergens with all their immunological sequelae. It is probable that these three mechanisms explain most, if not all, of the actions of phenothiazine.

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