SUMMARY Carcinoma of the urinary bladder is the most common malignancy in the Middle East and parts of Africa where schistosomiasis is a widespread problem. Much evidence supports the association between schistosomiasis and bladder cancer: this includes the geographical correlation between the two conditions, the distinctive patterns of gender and age at diagnosis, the clinicopathological identity of schistosome-associated bladder cancer, and extensive evidence in experimentally infected animals. Multiple factors have been suggested as causative agents in schistosome-associated bladder carcinogenesis. Of these, N-nitroso compounds appear to be of particular importance since they were found at high levels in the urine of patients with schistosomiasis-associated bladder cancer. Various strains of bacteria that can mediate nitrosation reactions leading to the formation of N-nitrosamines have been identified in the urine of subjects with schistosomiasis at higher intensities of infection than in normal subjects. In experimental schistosomiasis, the activities of carcinogen-metabolizing enzymes are increased soon after infection but are reduced again during the later chronic stages of the disease. Not only could this prolong the period of exposure to activated N-nitrosamines, but also inflammatory cells, sitmulated as a result of the infection, may induce the endogenous synthesis of N-nitrosamines as well as generating oxygen radicals. Higher than normal levels of host cell DNA damage are therefore anticipated, and they have indeed been observed in the case of alkylation damage, together with an inefficiency in the capacity of relevant enzymes to repair this damaged DNA. In experimental schistosomiasis, it was also found that endogenous levels of host cell DNA damage were related to the intensity of infection. All of these factors could contribute to an increased risk of bladder cancer in patients with schistosomiasis, and in particular, the gene changes observed may have potential for use as biomarkers in the early detection of bladder cancer that may assist in alleviating the problem.

Defective sperm function is the most common cause of infertility, and until recently, was difficult to evaluate and treat. Mammalian spermatozoa membranes are rich in poly unsaturated fatty acids and are sensitive to oxygen induced damage mediated by lipid peroxidation. Hence, free radicals and reactive oxygen species [ROS] are associated with oxidative stress and are likely to play a number of significant and diverse roles in reproduction. The excessive generation of reactive oxygen species by abnormal spermatozoa and by contaminating leukocytes [leukocytospermia] has been identified as one of the few defined etiologies for male infertility. Moreover, environmental factors, such as pesticides, exogenous estrogens, and heavy metals may negatively impact spermatogenesis since male sperm counts were declined. In addition, aging is also likely to further induce oxidative stress. Limited endogenous mechanisms exist to reverse these damages. In a normal situation, the seminal plasma contains antioxidant mechanisms which are likely to quench these ROS and protect against any likely damage to spermatozoa. However, during genitourinary infection/inflammation these antioxidant mechanisms may downplay and create a situation called oxidative stress. Assessment of such oxidative stress status [OSS] may help in the medical treatment of male infertility by suitable antioxidants. The cellular damage in the semen is a result of an improper balance between ROS generation and scavenging activities. Therefore, numerous antioxidants such as vitamin C, vitamin E, glutathione, and coenzyme Q10, have proven beneficial effects in treating male infertility. A multi-faceted therapeutic approach to improve male fertility involves identifying harmful environmental and occupational risk factors, while correcting underlying nutritional imbalances to encourage optimal sperm production and function.

Calcium ion is an essential structural component of the skeleton. There is growing evidence for the importance of nutrition in the maintenance of bones and joints health. Nutritional imbalance combined with endocrine abnormalities may be involved in osteoporosis. For example, essential fatty acids and their metabolites were reported to have beneficial action in osteoporosis. The mechanism by which fatty acids prevent osteoporosis may involve inhibition of pro-inflammatory cytokines, which are known to have a major role in osteoporosis through induction of oxidative stress which had adverse effects on the skeleton. Other risk factors for osteoporosis, such as smoking, hypertension and diabetes mellitus are also associated with increased oxidative stress and free radicals levels. When bone fracture occurs, a remarkable yield of free radicals is generated by the damaged tissues. However, controlled production of free radicals by normally functioning osteoclasts could accelerate destruction of calcified tissues and assist bone remodeling. Enhanced osteoclastic activity observed in bone disorders may have been responsible for increased production of reactive oxygen species [ROS] in the form of superoxide, which is evident by increased levels of serum malondialdehyde [MDA] levels. One of the most damaging effects of ROS is lipid peroxidation, the end product of which is MDA which also served as a measure of osteoclastic activity. Inhibition of the antioxidant enzymes activities, such as superoxide dismutase and glutathione peroxidase, was found to increase superoxide production by the osteoclasts which represented by increased levels of MDA. Therefore, oxidative stress is an important mediator of bone loss since deficiency of antioxidant vitamins has been found to be more common in the elderly osteoporotic patients. It is concluded from this review that increased free radical production overwhelms the natural antioxidants defense mechanisms, subjecting individuals to hyperoxidant stress and thus leading to osteoporosis. In addition, administration of antioxidants might protect bones from osteoporosis and also might help in the acceleration of healing of fractured bones.

Drug-metabolizing enzymes are called mixed-function oxidase or monooxygenase and containing many enzymes including cytochrome P450, cytochrome b5, and NADPH-cytochrome P450 reductase and other components. The hepatic cytochrome P450s (Cyp) are a multigene family of enzymes that play a critical role in the metabolism of many drugs and xenobiotics with each cytochrome isozyme responding differently to exogenous chemicals in terms of its induction and inhibition. For example, Cyp 1A1 is particularly active towards polycyclic aromatic hydrocarbons (PAHs), activating them into reactive intermediates those covalently bind to DNA, a key event in the initiation of carcinogenesis. Likewise, Cyp 1A2 activates a variety of bladder carcinogens, such as aromatic amines and amides. Also, some forms of cytochrome P450 isozymes such as Cyp 3A and 2E1 activate the naturally occurring carcinogens (e.g. aflatoxin B1) and N-nitrosamines respectively into highly mutagenic and carcinogenic agents. The carcinogenic potency of PAHs, and other carcinogens and the extent of binding of their ultimate metabolites to DNA and proteins are correlated with the induction of cytochrome P450 isozymes. Phase II drug-metabolizing enzymes such as glutathione S-transferase, aryl sulfatase and UDP-glucuronyl transferase inactivate chemical carcinogens into less toxic or inactive metabolites. Many drugs change the rate of activation or detoxification of carcinogens by changing the activities of phases I and II drug-metabolizing enzymes. The balance of detoxification and activation reactions depends on the chemical structure of the agents, and is subjected to many variables that are a function of this structure, or genetic background, sex, endocrine status, age, diet, and the presence of other chemicals. It is important to realize that the enzymes involved in carcinogen metabolism are also involved in the metabolism of a variety of substrates, and thus the introduction of specific xenobiotics may change the operating level and the existence of other chemicals. The mechanisms of modification of drug-metabolizing enzyme activities and their role in the activation and detoxification of xenobiotics and carcinogens have been discussed in the text.

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Cancer development results from the interaction between genetic factors, the environment, and dietary factors have been identified as modulators of carcinogenesis process. The formation of DNA adducts is recognized as the initial step in chemical carcinogenesis. Accordingly, blocking DNA adducts formation would be the first line of defense against cancer caused by carcinogens. Glutathione-S-transferases inactivate chemical carcinogens into less toxic or inactive metabolite through reduction of DNA adducts formation. There are many different types of glutathione S-transferase isozymes. For example, GST delta serves as a marker for hepatotoxicity in rodent system, and also plays an important role in carcinogen detoxification. Therefore, inhibition of GST activity might potentiate the deleterious effects of many environmental toxicants and carcinogens. In addition, approximately half of the population lacks GST Mu expression. Epidemiological evidence showed that persons possessing this genotype are predisposed to a number of cancers including breast, prostate, liver and colon cancers. In addition, individual risk of cancer depends on the frequency of mutational events in target oncogenes and tumor suppressor genes which could lead to loss of chromosomal materials and tumor progression. The most frequent genetic alteration in a variety of human malignant tumors is the mutation of the coding sequence of the p53 tumor suppressor gene. O(6)-alkylguanine in DNA leads to very high rates of G:C deltaA:T transitions in p53 gene. These alterations will modulate the expression of p53 gene and consequently change DNA repair, cell division, and cell death by apoptosis. Also, changes in the expression of BcI-2 gene results in extended viability of cells by over-riding programmed cell death (apoptosis) induced under various conditions. The prolonged life-span increases the risk of acquiring genetic changes resulting in malignant transformation. In addition, a huge variety of food ingredients have been shown to affect cell proliferation rates. They, therefore, may either reduce or increase the risk of cancer development and progression. For example, it has been found that a high intake of dietary fat accelerates the development of breast cancer in animal models. Certain diets have been suggested to act as tumor promoters also in other types of cancer such as colon cancer, where high intake of fat and phosphate have been linked to colonic hyper-proliferation and colon cancer development. Different factors such as oncogenes, aromatic amines, alkylating agents, and diet have a significant role in cancer induction. Determination of glutathione S-transferase isozymes in plasma or serum could be used as a biomarker for cancer in different organs and could give an early detection.