Unifying mechanism for toxicity and addiction by abused drugs: electron transfer and reactive oxygen species

Abstract

Abused drugs are of grave concern throughout the world for a variety of reasons. Although impressive advances have been made, there are many unknown mechanistic aspects. This report presents a novel hypothesis based on a unifying theme for action of the major classes of abused drugs, in addition to commonly abused therapeutic drugs. The approach is based on electron transfer (ET), reactive oxygen species (ROS), and oxidative stress (OS). It is significant that physiologically active substances generally incorporate ET functionalities, either per se, or more usually in their metabolites. In order to achieve ET in vivo, the reduction potential must be more positive than -0.5 V, which is the case for metabolites of abused drugs, except for special cases. Since the ET process is catalytic, only small quantities of agent are needed for generation of large amounts of ROS during redox cycyling. Bioaction with cellular materials could entail ET alone or participation of ROS. In the abused category, among the main classes of ET functionalities are quinones and iminiums, with alpha-dicarbonyl and nitroxyl radical being rarer. Nicotine yields nicotine iminium, myosmine iminium, and DNA base iminium via alkylation by a metabolic nitrosamine. In the case of alcohol, diacetyl (an alpha-dicarbonyl) is formed, which can lead to conjugated imine (or iminium) by condensation with pri-amine of protein. Phencyclidine is unusual since the iminium product is non-conjugated. However, data indicate that the conformation present at the binding site can accommodate delocalization of the derived radical. For cocaine, various metabolites may play a role: iminium, nitroxyl radical, nitrosonium and formaldehyde. Dealkylation of the ether moiety of ecstasy provides a catechol function capable of redox cycling with the o-quinone partner. Amphetamine and methamphetamine also appear to function by way of the catechol route, as well as morphine and heroin. Tetrahydrocannabinol produces an epoxide, a functionality capable of DNA base alkylation accompanied by ROS. LSD undergoes oxidation to a phenol which may be a quinone precursor. Therapeutic drugs display the indicated metabolic relationships: benzodiazepines, iminium; phenytoin, quinone; phenobarbital, catechol; aspirin, catechol and hydroquinone; acetaminophen, iminoquinone. Extensive evidence exists for formation of ROS, organ injury by OS, depletion of AOs, and protection by AOs for the various drugs. There is also discussion of computational approaches, addiction mechanism and prevention, and health promotion.