Pharmacological uses and perspectives of heavy water and deuterated compounds

Abstract

Since the discovery of D20 (heavy water) and its use as a moderator in nuclear reactors, its biological effects have been extensively, although seldom deeply, studied. This article reviews these effects on whole animals, animal cells, and microorganisms. Both "solvent isotope effects," those due to the special properties of D20 as a solvent, and "deuterium isotope effects" (DIE), which result when D replaces H in many biological molecules, are considered. The low toxicity of D20 toward mammals is reflected in its widespread use for measuring water spaces in humans and other animals. Higher concentrations (usually >20% of body weight) can be toxic to animals and animal cells. Effects on the nervous system and the liver and on formation of different blood cells have been noted. At the cellular level, D20 may affect mitosis and membrane function. Protozoa are able to withstand up to 70% D20. 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 result of inhibition of chaperonin formation. High D2O concentrations can reduce salt- and ethanol-induced hypertension in rats and protect mice from gamma irradation. Such concentrations are also used in boron neutron capture therapy to increase neutron penetration to boron compounds bound to malignant cells. D2O is more toxic to malignant than normal animal cells, but at concentrations 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 different actions than the protonated forms. Some deuterated drugs show different transport processes. Most are more resistant to metabolic changes, especially those changes mediated by cytochrome P450 systems. Deuteration may also change the pathway of drug metabolism (metabolic switching). Changed metabolism may lead to increased duration of action and lower toxicity. It may also lead to lower activity, if the drug is normally changed to the active form in vivo. Deuteration can also lower the genotoxicity of the anticancer drug tamoxifen and other compounds. Deuteration increases effectiveness of long-chain fatty acids and fluoro-D-phenylalanine by preventing their breakdown by target microorganisms. A few deuterated antibiotics have been prepared, and their antimicrobial activity was found to be little changed. Their action on resistant bacteria has not been studied, but there is no reason to believe that they would be more effective against such bacteria. Insect resistance to insecticides is very often due to insecticide destruction through the cytochrome P450 system. Deuterated insecticides might well be more effective against resistant insects, but this potentially valuable possibility has not yet been studied.

Nuclear Quantum Effects in Water and Aqueous Systems: Experiment, Theory, and Current Challenges

“…At the outset it is interesting to note that water's seeming ambivalence to quantum effects for some properties is reflected in the fact that prokaryotic organisms such as bacteria can tolerate pure D 2 O conditions (43), while deuterating about 30% of plant's and mammal's water can be lethal (44)(45)(46).…”

Determining Degradation and Synthesis Rates of Arabidopsis Proteins Using the Kinetics of Progressive 15N Labeling of Two-dimensional Gel-separated Protein Spots

“…SILAC has also been used to measure protein turnover in yeast but required the use of auxotrophic mutants (5). However, this approach is problematic in plants that actively synthesize all of their amino acids de novo, which dilutes and mixes the label between amino acids and leads to inefficient incorporation into proteins (15,16 18 O, 15 N, or 13 C can be used to label whole plants and de novo synthesis tracked by the increase in the mass of the resulting proteins (9,17). Deuterium oxide has been used to study labeling at the protein and amino acid levels (8,9).…”

“…The advantage of deuterium labeling is that it rapidly enters cellular compartments and equilibrates with the water environment. However, 2 H 2 O is not biologically benign, and multicellular organisms are limited in the percentage of deuterium oxide they tolerate (8,9,18). …”

Is Liquid Water a Hot Quantum Fluid? Anomalies of Water in Thin Liquid Films and in Biological Systems

“…The toxicity of heavy water has been widely reported. 27 This toxicity is not a difference in chemistry, but perhaps can be explained as follows. The thermal wavelength of D2O or HOD is shorter than that of H2O.…”