Volume 1 (2008): Issue 1 (June 2008)

The most important enzymes of detoxication are cytochromes P450 of Phase I and UDPglucuronosyltransferases of Phase II of drug metabolism. The conventional division of drug, or xenobiotic, metabolism to two phases has survived almost fifty years and although not perfect, still is rather informative and practical. The recent addition of the next, third phase to the first two (Phase I as yielding a molecule with free functional groups ready for conjugation with another molecule or its part in Phase II) stressed the importance of drug transport across the membranes even if it is not a pure metabolic process (i.e. a process changing the polarity and structure of a compound).

Ingestion of aristolochic acid (AA) is associated with the development of aristolochic acid nephropathy, which is characterized by chronic renal failure, tubulointerstitial fibrosis and urothelial cancer. AA may also cause a similar type of kidney fibrosis with malignant transformation of the urothelium, the Balkan endemic nephropathy. Understanding which enzymes are involved in AA activation and/or detoxication is important in the assessment of a susceptibility to this carcinogen. The most important human enzymes activating AA by simple nitroreduction in vitro are hepatic and renal cytosolic NAD(P)H:quinone oxidoreductase, hepatic microsomal cytochrome P450 1A2 and renal microsomal NADPH:cytcohrome P450 reductase, besides cyclooxygenase, which is highly expressed in urothelial tissue. Despite extensive research, contribution of most of these enzymes to the development of these diseases is still unknown. Hepatic cytochromes P450 were found to detoxicate AA in mice, and thereby protect the kidney from injury. However, which of cytochromes P450 are the most important in this process both in animal models and in humans have not been entirely resolved as yet. In addition, the relative contribution of enzymes found to activate AA to species responsible for induction of urothelial cancer in humans remains still to be resolved.

Genotoxicology investigates the molecular basis of cellular responses to DNA damage. During more than three decades of genetic toxicology testing, a large number of tests with varying sensitivity and specificity have been developed.

These genotoxicity tests can predict:

the likelihood of a substance to be a (rodent) carcinogen,

the mechanism of carcinogenic activity of different substances,

if the results of genotoxicity studies only predict carcinogenicity or they are a distinct hazard endpoint (Nohynek, 2005).

The current genetic toxicity testing batteries represent:

Ames test which is a component of all genetic testing batteries.

A mammalian cell mutagenicity assay which should confirm or complete the Ames test.

Chromosomal aberrations tests which are based on a different endpoint than gene mutations.

Positive in vitro results need to be confirmed by in vivo tests; results from test batteries have higher predictive value than results of a single test (Nohynek, 2005).

Committee accepted the program of chemical safety in October 2003 called REACH, meaning "Registration, Evaluation, Authorization of Chemicals". The protection of health of nature, including human beings, against harmful effects of chemicals is a goal of these programs. The development and research on new chemicals can become, however, cheaper than their testing and registration. The aim of effort of the present is, thus, to develop and to use alternative methods of testing toxic and adverse effects of chemicals, which would be cheaper and more informative than traditional tests with experimental animals.

Nerve agents belong to highly toxic organophosphorus compounds misused as chemical warfare agents for military as well as terroristic purposes. Basic mechanism of action of nerve agents is based on acetylcholinesterase (AChE, EC 3.1.1.7) inhibition and subsequent accumulation of neuromediator acetylcholine at the cholinergic synapses, either peripheral or central leading to cholinergic hyperstimulation and development of symptoms of poisoning, followed by metabolic dysbalance and death without effective prophylaxis/treatment. The antidotal treatment of acute poisonings with nerve agents still represents a serious problem and, therefore, we are searching how to satisfactorily protect people against acute toxicity of nerve agents. There are two approaches how to improve the medical protection against nerve agents:

to increase the resistance of nerve agent-exposed organism and the efficacy of post-exposure antidotal treatment by pharmacological prophylaxis

the development of new, more effective antidotes, expecially AChE reactivators, to achieve the satisfactorily effective antidotal treatment of acute poisonings with nerve agents.

Sulfur mustard (SM), also known as mustard gas, has been the most widely used chemical weapon. The toxicity of SM as an incapacitating agent is of much greater importance than its ability to cause lethality. Acute toxicity of SM is related to reactive oxygen and nitrogen species, DNA damage, poly(ADP-ribose) polymerase activation and energy depletion within the affected cell. Therefore melatonin shows beneficial effects against acute SM toxicity in a variety of manner. It scavenges most of the oxygen- and nitrogen-based reactants, inhibits inducible nitric oxide synthase, repairs DNA damage and restores cellular energy depletion. The delayed toxicity of SM however, currently has no mechanistic explanation. We propose that epigenetic aberrations may be responsible for delayed detrimental effects of mustard poisoning. Epigenetic refers to the study of changes that influence the phenotype without causing alteration of the genotype. It involves changes in the properties of a cell that are inherited but do not involve a change in DNA sequence. It is now known that in addition to genetic mutations, epimutations can also involve in the pathogenesis of a variety of human diseases. Several actions of melatonin are now delineated by epigenetic actions including modulation of histone acetylation and DNA methylation. Future studies are warranted to clarify whether epigenetic mechanisms are involved in pathogenesis of delayed sulfur mustard toxicity and melatonin alleviates delayed toxicity of this warfare agent.

Studies of individual development and its possible deterioration have been the concern since the 19th century, when Etienne Geoffroy de Saint-Hilaire (1772-1844) with his pioneer experiments opened the door for future experimental teratologists. Later scientists, focused on environmental agents which can alter embryonic and fetal development, such hyperthermia, malnutrition, pharmaceuticals, microbial toxins etc. Although the history of teratology involves many notable scientists, it has gained prominence after the big thalidomide tragedy in 1961. Principles of teratology were proposed later by James Wilson in his monograph Environment and Birth Defects (Wilson, 1973).

Human epidemiological and experimental animal studies show that suboptimal environments in fetal and neonatal life exerts a profound influence on physiological function and risk of disease in adult life. The molecular, cellular, metabolic, endocrine and physiological adaptations to intrauterine nutritional conditions result in permanent alterations of cellular proliferation and differentiation of tissues and organ systems, which in turn can manifest by pathological consequences or increased vulnerability to chronic diseases in adulthood. Intrauterine growth restriction (IUGR) due to intrauterine development derangements is considered the important factor in development of such diseases as essential hypertension, diabetes mellitus, ischemic diseases of the heart, osteoporosis, respiratory, neuropsychiatric and immune system diseases.

An early life exposures to dietary and environmental exposures can have a important effect on epigenetic code, resulting in diseases developed later in life. The concept of the "developmental programming" and Developmental Origins of Adult Diseases (DOHaD) has become well accepted because of the compelling animal studies that have precisely defined the outcomes of specific exposures. The environmental pollullutants and other chemical toxicants may influence crucial cellular functions during critical periods of fetal development and permanently alter the structure or function of specific organ systems. Developmental epigenetics is believed to establish "adaptive" phenotypes to meet the demands of the later-life environment. Resulting phenotypes that match predicted later-life demands will promote health, while a high degree of mismatch will impede adaptability to later-life challenges and elevate disease risk. The rapid introduction of synthetic chemicals, environmental pollutants and medical interventions, may result in conflict with the programmed adaptive changes made during early development, and explain the alarming increases in some diseases.