Pharmacological uses and perspectives of heavy water and deuterated compounds

Since the discovery of D2O (heavy water) and its use as a moderator in nucl ear reactors, its biological effects have been extensively, although seldom deeply, studied. This article reviews these effects on whole animals, anim al cells, and microorganisms. Both "solvent isotope effects," those due to the special properties of D2O as a solvent, and "deuterium isotope effects" (DIE), which result when D replaces H in many biological molecules, are co nsidered. The low toxicity of D2O toward mammals is reflected in its widesp read use for measuring water spaces in humans and other animals. Higher con centrations (usually >20% of body weight) can be toxic to animals and anima l cells. Effects on the nervous system and the liver and on formation of di fferent blood cells have been noted. At the cellular level, D2O may affect mitosis and membrane function. Protozoa are able to withstand up to 70% D2O . Algae and bacteria can adapt to grow in 100% D2O and can serve as sources of a large number of deuterated molecules. D2O increases heat stability of macromolecules but may decrease cellular heat stability, possibly as a res ult of inhibition of chaperonin formation. High D2O concentrations can redu ce salt- and ethanol-induced hypertension in rats and protect mice from gam ma irradation. Such concentrations are also used in boron neutron capture t herapy to increase neutron penetration to boron compounds bound to malignan t cells. D2O is more toxic to malignant than normal animal cells, but at co ncentrations too high for regular therapeutic use. D2O and deuterated drugs are widely used in studies of metabolism of drugs and toxic substances in humans and other animals. The deuterated forms of drugs often have differen t actions than the protonated forms. Some deuterated drugs show different t ransport processes. Most are more resistant to metabolic changes, especiall y those changes mediated by cytochrome P450 systems. Deuteration may also c hange the pathway of drug metabolism (metabolic switching). Changed metabol ism may lead to increased duration of action and lower toxicity. It may als o lead to lower activity, if the drug is normally changed to the active for m in vivo. Deuteration can also lower the genotoxicity of the anticancer dr ug tamoxifen and other compounds. Deuteration increases effectiveness of lo ng-chain fatty acids and fluoro-D-phenylalanine by preventing their breakdo wn by target microorganisms. A few deuterated antibiotics have been prepare d, and their antimicrobial activity was found to be little changed. Their a ction on resistant bacteria has not been studied, but there is no reason to believe that they would be more effective against such bacteria. Insect re sistance to insecticides is very often due to insecticide destruction throu gh the cytochrome P450 system. Deuterated insecticides might well be more e ffective against resistant insects, but this potentially valuable possibili ty has not yet been studied.