Iminium metabolite mechanism for nicotine toxicity and addiction: Oxidative stress and electron transfer.

The mechanism of nicotine toxicity is not completely delineated. Considerable evidence points to involvement of oxidative stress (OS), reactive oxygen species, lipid peroxidation, DNA damage, and beneficial effect of antioxidants. Previously, a suggestion was advanced for participation of iminium metabolites which might operate, via electron transfer (ET) with redox cycling, to produce radical entities. The conjugated iminium functionality is one of the less well-known ET types. The cationic metabolites arise from several routes, including oxidation of nicotine itself, and protonation of myosmine which originates from nornicotine via demethylation of nicotine. Reduction potentials, which are in the range amenable to ET in vivo, lend credence to the theoretical framework. An alternate metabolic route entails hydrolysis of nicotine iminium to an open-chain ketoamine that, in turn, undergoes nitrosation to form a toxic nitrosamine. Subsequently, the nitrosamine serves as a DNA alkylator which can also generate conjugated iminiums by attack on certain nitrogens of DNA bases. During the past 14 years, the hypothesis has enjoyed substantial support. Increasing evidence points to a role for OS in toxicity by nicotine entailing major body organs, including the lung, cardiovascular system, central nervous system, liver, kidney, testes, ovary, pancreas, and esophagus. The mechanism of addiction is also addressed based on interaction of iminiums with normal electron transport chains or electrical phenomena in the brain. The process might occur with or without participation of reactive oxygen species. Evidence indicates that free radicals are widely involved in cell signaling entailing redox processes in the categories of ion transport, neuromodulation, and transcription. Low levels of radicals appear to participate since high concentrations are associated with toxicity. Various possibilities for future work based on the hypothetical approach are addressed, including some that may have practical utility in relation to health improvement, toxicity, and addiction. Insight should be gained from computational studies on the energetics of electron uptake by metabolic iminiums, and on stability of the resultant delocalized radicals. Additional large-scale investigations of antioxidant effects are needed in order to resolve prior conflicting reports. Other proposals are based on interference with metabolism to iminiums and nitrosamines, and destruction of harmful metabolites. Since the iminium entities are proposed to play crucial, adverse roles, it would be worthwhile to explore them with regard to receptors, physiological activities, possible generation of reactive oxygen species, and effect of antioxidants.

Mechanisms of carcinogenesis: focus on oxidative stress and electron transfer.

For more than half a century, numerous proposals have been advanced for the mode of action of carcinogens. This review presents a wide array of evidence that implicates oxidative stress (OS) in many aspects of oncology, including: formation of reactive oxygen species (ROS) by the major classes of carcinogens (as well as minor ones), cancer stages, oncogene activation, aging, genetic and infectious illnesses, nutrition, and the role of antioxidants (AOs). Although diverse origins pertain, including both endogenous and exogenous agents, ROS are frequently generated by redox cycling via electron transfer (ET) groups, e.g., quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced products), and conjugated imines (or iminium species). We believe it is not coincidental that these functionalities are often found in carcinogens or their metabolites. The pervasive aspects of DNA binding by ultimate carcinogens, and mutations caused by ROS are treated. Often, ROS are implicated in more conventional rationales, such as oncogenes. A multi-faceted approach to mechanisms appears to be the most logical. The OS unifying theme represents an approach which is able to rationalize the diverse data associated with carcinogenesis. Because this theoretical framework aids in the understanding of cancer initiation, it can serve as a useful tool in combating cancer, particularly in relation to prevention. Significantly, the electron transfer--oxidative stress (ET-OS) scenario can also be applied to many drug categories, toxins, enzymes, and hormones.

Reproductive toxins: pervasive theme of oxidative stress and electron transfer.

Reproductive toxicity has been a topic of increasing interest and concern in recent years, generating controversy in association with danger to humans and other living things. A veritable host of chemicals is known to be involved, encompassing a wide variety of classes, both organic and inorganic. Exposure is pervasive and virtually unavoidable due to contamination of air, water, ground, food, beverages, drugs, and household items. The corresponding adverse effects on reproduction are numerous. There is uncertainty regarding mode of action although various theories have been advanced, e.g., disruption of the CNS, DNA attack, enzyme inhibition, interference with hormonal action, and insult to membranes and proteins. This review provides extensive evidence for involvement of oxidative stress (OS) and electron transfer (ET) as a unifying theme. Successful application is made to all of the main classes of toxins, in addition to large numbers of miscellaneous types. We believe it is not coincidental that the vast majority of these substances incorporate ET functionalities (quinone, metal complex, ArNO2, or conjugated iminium) either per se or in metabolites, potentially giving rise to reactive oxygen species (ROS) by redox cycling. Some categories, e.g., peroxides and radiation, appear to generate ROS by non-ET routes. For completeness, other theories are also addressed; a multifaceted approach appears to be the most logical. Our framework should increase understanding and contribute to preventative measures, such as use of antioxidants (AOs). The ET-OS theory has recently been used as the central theme by us in reviews of biomechanisms involved with anti-infective drugs, anticancer agents, and carcinogens.

Review: DNA molecular electrostatic potential: novel perspectives for the mechanism of action of anticancer drugs involving electron transfer and oxidative stress.

This report examines the mechanism of action of DNA-binding anticancer drugs that involve electron transfer and oxidative stress, and primarily focuses on neglected issues surrounding molecular electrostatic potentials (MEP), the energetics of initial guanine oxidation and the consequences of the sequence dependence of DNA structure on electron transport within a DNA duplex. We argue that an appreciation of electrostatic effects aids in shaping a more complete view of the electron transfer and DNA oxidation process. Some aspects concerning the MEP of DNA relevant to these events have lain dormant, whereas others represent novel insights. We discuss the impact of electrostatics on ligand binding to DNA, guanine oxidation, axial charge transport and hopping termination reactions. Another ignored feature for intercalating redox-active agents is the reversible nature of their interaction with DNA, which in principle permits catalytic regeneration of the unmodified ligand via redox cycling with generation of reactive oxygen species. Therefore, oxidative stress may be exerted on DNA at both ends of the charge transport chain. Hence, mechanistic treatments that neglect to take into account the importance of the MEP of DNA may be flawed or deficient in many cases. An increased understanding of the basic mechanisms of redox chemistry within DNA may aid in improved anticancer drug design.

Mode of action of anti-infective agents: focus on oxidative stress and electron transfer.

There is increasing evidence for involvement of oxidative stress (OS) in the mechanism of action of a wide variety of physiologically active materials. Often the reactive oxygen species (ROS) are generated by electron transfer (ET) or other routes mediated by free radicals. Principal ET functionalities are quinones (or precursors), metal complexes, aromatic nitro compounds (ArNO2), and conjugated imines. These moieties are commonly found in the structures of anti-infective agents or their metabolites. In most cases, the ET functionalities display reduction potentials in the physiologically active range, i.e. more positive than approximately -0.5 V. Though the focus of this review is on OS and ET, a mode of action which emulates the natural immune system of the host, in some cases, this mechanism also appears to be involved in more generally accepted approaches, such as enzyme inhibition, adverse effects on membranes and DNA, or interference with DNA or protein synthesis. OS-ET represents a broad understanding of drug action that can aid in the design of new anti-infective agents. It is significant that a relatively simple unifying theme can be applied not only to the action of the predominant groups of anti-infective agents, but also more generally to other drug classes, toxins, carcinogens, enzymes, and hormones.

Mechanisms of anti-cancer agents: emphasis on oxidative stress and electron transfer.

A large body of evidence has accumulated indicating involvement of oxidative stress (OS) in the mode of action of various bioactive substances, including those of the immune system. The data for anticancer drugs (main and miscellaneous) are summarized herein. Although diverse origins pertain, reactive oxygen species (ROS) are frequently generated by redox cycling via electron transfer (ET) groups, such as quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced products) and conjugated imines (or iminium species). We believe it is not coincidental that these functionalities are frequently found in anticancer agents or their metabolites. Generally, the ET moieties display reduction potentials in the physiologically active range. Often ROS are also implicated in more traditional rationales, namely, enzyme inhibition, membrane or DNA insult, and interference with DNA or protein synthesis. A multi-faceted approach to mechanism appears to be the most logical. Significantly, the unifying theme of ET-OS also applies to other drug categories, as well as to toxins, carcinogens, hormones, and enzymes. Since this theoretical framework aids in our understanding of drug action, it can serve as a useful tool in the design of more active and safer pharmaceuticals.

Phagomimetic action of antimicrobial agents.

A wide variety of extracted and synthesised drug molecules have electron transfer capabilities which allow them to generate reactive oxygen species (ROS). In particular, many antibiotics that kill or inhibit bacteria, yeasts and cancer cells readily transfer electrons to oxygen making superoxide and hydrogen peroxide in the process. When suitable redox active forms of iron are available, Fenton chemistry occurs generating the highly damaging hydroxyl radical. This type of chemistry is very similar to that which evolved within phagocytic cells as part of their microbial killing armoury. Many antibiotics, when used in model systems, have well defined pharmacological actions against key cellular functions, but their clinical usefulness is also often demonstrable at concentrations in vivo well below their in vitro minimum inhibitory concentrations. These observations have led us to propose that a common mechanism exists whereby phagocytic cells and antibiotics exploit the use of ROS for microbial killing.

Electrochemistry of anticonvulsants: electron transfer as a possible mode of action.

Reduction potentials were determined for various anticonvulsants, including progabide, SL 75.102, CGS 9896, pyridazines, zonisamide, 1,2,3-triazoles, and copper complexes. The values generally were in the range of about -0.1 to -0.6 V for the protonated drugs and the metal complexes. Reduction potentials provide information on the feasibility of electron transfer (ET) in vivo. If the value is relatively positive (greater than about -0.6 V), the agent can act catalytically as an electron acceptor from an appropriate cellular donor. A concomitant favorable influence on abnormal neuronal processes associated with epilepsy could occur. We describe ET as a possible mode of action of anticonvulsants as well as some antiepileptic agents with no electrochemical data based on this hypothetical ET approach.

Electrochemistry of Cu(I) bipyridyl complexes with alkene, alkyne, and nitrile ligands. Implications for plant hormone action of ethylene.

The redox behavior was evaluated for several (BIPY)Cu(I) complexes (BIPY = 2,2'-bipyridyl) with unsaturated ligands by means of cyclic voltammetry in CH2Cl2 at reduced temperatures (-78 degrees, -23 degrees, 0 degree C). The complexes studied are [Cu(I)(BIPY)(C2H4)]PF6, [Cu(I)(BIPY)(3-hexyne)] PF6, [Cu(I)(BIPY)(DEAD)]PF6, ([Cu(I)(BIPY)]2 DEAD)[PF6]2 (DEAD = diethyl acetylene dicarboxylate) and [Cu(I)(BIPY)(CH3CN)]PF6. The oxidations are quasi-reversible at -78 degrees C for scan rates of 20 to 200 mV/sec. The reductions were irreversible on the CV time scale. Evidence is presented in support of a role for an electron transfer mechanism in the case of the plant hormone ethylene. Related literature data are also discussed.

Theoretical studies on mechanism of MPTP action: ET interference by MPP+ (1-methyl-4-phenylpyridinium) with mitochondrial respiration vs. oxidative stress.

This report demonstrates that ease of electron uptake by 1-methyl-4-phenylpyridinium (MPP+), apparently the active agent derived from MPTP, is influenced by conformation of the phenyl ring. From quantum mechanical calculations on MPP+, electron affinity is most negative for the nearly coplanar arrangement, indicating that the molecule is most readily reduced in this geometry. Ionization potential is largest in the perpendicular conformation, thus making for most facile oxidation in that form. Site binding would be expected to alter conformation in comparison with the situation in solution, and, hence, to influence reduction potential. We suggest that electron transfer by MPP+ may play a role in inhibition of mitochondrial respiration and in oxidative stress.

Are reduction potentials of antifungal agents relevant to activity?

Cyclic voltammetry data were obtained for several categories of fungicidal agents including quinones (akrobomycin, podosporin A), iminium ions and precursors (pyridazines, 15-azahomosterol, griseofulvin-4'-oxime), and metal derivatives of chelators (pyridine-2-aldehyde thiosemicarbazones). The reductions usually occurred in the range of -0.7 to +0.3 V. Reduction potentials provide information on the feasibility of electron transfer in vivo. Catalytic production of oxidative stress from redox cycling is a possible mode of action. Alternatively, there may be interference with normal electron transport chains.

Theoretical calculations on calcium channel drugs: is electron transfer involved mechanistically?

Theoretical studies were done on calcium channel drugs in order to gain insight into the mode of action. Empirical force field calculations with nifedipine, a calcium channel antagonist, indicate that the E-conformation at the ring juncture is lower in energy than the Z-conformation. This energy difference is only 0.2 kcal/mol when the esters in the 3- and 5-positions of the dihydropyridine (DHP) ring are both synperiplanar (sp, sp). Molecular orbital calculations on the ground and excited states in the Z-conformation with the esters in the (ap, sp) conformation show a low lying excited state with substantial intramolecular electron transfer (ET) character. This excited state is only 1.8 eV higher in energy than the ground state and corresponds to a transfer of approximately 0.3 electron from the DHP ring to the nitrobenzene moiety. We suggest that ET may play an important role in the mechanism of action, either intramolecular or, as previously proposed, intermolecular, along with lipophilicity and steric effects.

Reduction potentials of imine-substituted, biologically active pyridines: possible relation to activity.

Cyclic voltammetry data were obtained for a number of biologically active compounds which incorporate imine substitution on the pyridine nucleus. The reductions in acid (iminium ion formation) were for the most part reversible, and in the range of -0.5 to -0.7V. The toxic effect of these drugs is thought to be caused by the generation of reactive oxygen radicals that arise via charge transfer, or by disruption of electron transport chains.

Electrochemistry of cyclic alpha-imino carboxylates and their metal complexes: correlation with physiological activity.

Cyclic voltammetry data were obtained for delta 1-pyrroline-2-carboxylate, delta 3-thiazoline-4-carboxylate, delta 2-thiazoline-2-carboxylate and their complexes with Cu(II), Fe(III), and Fe(II). The free ligands were reduced at about -0.35 V and were oxidized in the range of 0.42-0.52 V. Complexing the imine carboxylates with metal ions produces reduction and oxidation in the ranges of 0.05-0.37 V and 0.52-0.74 V, respectively. Prior reports show that these ligands take part in various biological functions. We propose that electron transfer may be involved in some aspects of the physiological activity. The captodative effect can be applied.

Reduction potentials of anthelmintic drugs: possible relationship to activity.

Electrochemical data were acquired for several categories of anthelmintic agents, namely, iminium-type ions, metal derivatives and chelators, quinones and iminoquinones, and nitroheterocycles. Reductions usually were in the favorable range of +0.2 to -0.7 V versus normal hydrogen electrode. The drug effect is believed to result in part from either the catalytic production of oxidative stress or disruption of helminth electron transport systems. Relevant literature results are discussed.

Minimum essential structural requirements for lactam antibiotic action.

A mechanism of action encompassing mono- and bicyclic beta-lactams has been proposed previously, which stresses the importance of formation of an electron transfer (ET) entity (conjugated iminium) as a requirement for antibiotic activity, in association with enzyme inactivation. Additional evidence in support of this contention is now provided. Reduction potentials for several cephalosporins and pyrazolidinones, all of which contain an oximino functionality in the side chain, were observed in the range of -0.6 to -0.7 V. Comparison is made with related compounds lacking imine. Agents containing side chain hydrazone, oxamazins (mono beta-lactams), and lactivicin are discussed based on the ET approach.

Anti-cancer action of metal complexes: electron transfer and oxidative stress?

Evidence is presented in support of an electron transfer mechanism for various metal complexes possessing anti-neoplastic properties. Cyclic voltammetry was performed on several metallocenes, bis(acetato)bis(imidazole)Cu(II), and coordination compounds (Cu or Fe) of the antitumor agents, bipyridine, phenanthroline, hydroxyurea, diethyldithiocarbamate, and alpha, alpha'-bis(8-hydroxyquinolin-7-yl)-4-methoxytoluene. The favorable reduction potentials ranged from +0.5 to -0.5 Electrochemical behavior is correlated in some cases with structure and physiological activity. Relevant literature data are discussed.

Electrochemistry of the anticancer agents methotrexate and alpha-difluoromethylornithine in iminium form.

The electrochemical characteristics of the antitumor agents methotrexate and alpha-difluoromethylornithine were determined as their iminium derivatives. Iminium formation from methotrexate is accomplished in vivo via protonation by enzyme. The requisite imine precursor is generated from alpha-difluoromethylornithine by condensation with enzyme containing pyridoxal phosphate. Electroreduction occurs in the range of -0.2 to -0.6 V. The relationship of reduction to structure is discussed. A possible mode of anticancer action involving electron transfer is presented.

Mode of action of antiprotozoan agents. Electron transfer and oxy radicals.

Cyclic voltammetry data were obtained for most of the main classes of antiprotozoan agents, specifically, nitroheterocycles, quinones, metal complexes and derivatives, iminium-type ions, and azo compounds. The reductions were generally reversible in the range of -0.3 to -0.9 V. Catalytic production of oxidative pressure from redox cycling involving oxygen is believed to be an important mode of action by the medicinal agents. Literature data contribute support.

Electron transfer-oxy radical mechanism for anti-cancer agents: 9-anilinoacridines.

A possible mode of action involving electron transfer is advanced for the 9-anilinoacridines. The mechanism entails formation of toxic oxy radicals which destroy the neoplasm. Cyclic voltammetry was performed on iminium type ions derived by protonation of the acridines. Reductions were generally reversible with potentials of about -0.60 V. Involvement of quinoidal metabolites is also a possibility. The relationship of electrochemical behavior to structure and physiological activity is addressed.