Effects of Schistosoma haematobium infection on drug-metabolizing enzymes in human bladder cancer tissues.

The mixed function oxidase system includes the phase I drug oxidation proteins e.g. aryl hydrocarbon hydroxylase (AHH), N-nitrosodimethylamine-N-demethylase I (NDMA-dI) and cytochrome b5 which metabolize most carcinogens and xenobiotics into less and/or more active intermediates. These were determined in human bladder tissues diagnosed as bladder cancer only (10 samples) and bladder cancer associated with Schistosoma haematobium (12 samples) and normal bladder tissues (12 samples). In addition to the above enzymes, agents involved in Phase II drug metabolism e.g. glutathione and glutathione S-transferase as well as free radicals (detected as thiobarbituric acid-reactive substances, TBARS) were also determined in these tissues samples. AAH and NDMA-dI, cytochrome b5, and glutathione S-transferase activity decreased by 42, 28, 47 and 32%, respectively, in human bladder cancer tissues. In bladder cancer tissues associated with S. haematobium infection NDMA-dI and GST activity decreased further by 65 and 56%, respectively, whereas AHH activity increased by 50% and levels of reduced glutathione also increased by 43% in cancer tissue and by 29% in schistocome infected bladder cancer tissue. The level of free radicals also increased significantly (by 57%) in infected bladder cancer tissue but not at all in non-infected cancer tissue. Alterations in the activity of phase I and II of drug-metabolizing enzymes in human bladder tissues as a result of S. haematobium infection may therefore change the bladder's capacity to detoxify many endogenous compounds and may also potentiate the deleterious effects of bladder carcinogens, (e.g. N-nitrosamines) which are known to be present in relatively large quantities in the bladder of patients with schistosomiasis. The present study thus provides new insights into mechanisms for the genesis of bladder cancer initiated in association with schistosomiasis.

Changes in the expression of cytochrome P450 2E1 and the activity of carcinogen-metabolizing enzymes in Schistosoma haematobium-infected human bladder tissues.

The bioactivation of N-nitrosamines and polycyclic aromatic hydrocarbons (PAHs) is mediated primarily by the mixed-function oxidase system, which includes dimethylnitrosamine N-demethylase I, arylhydrocarbon [benzo(a)pyerne] hydroxylase, cytochrome P450, cytochrome b(5), and ethoxycoumarin deethylase. Most of carcinogens and xenobiotics are conjugated and detoxified by phase II drug-metabolizing enzymes such as glutathione S-transferase. The present study showed the influence of Schistosoma haematobium on the activity of the above-mentioned enzymes in 13 schistosome-infected human bladder tissues compared with those of 15 schistosome-free samples. The contents of cytochrome P450 and cytochrome b(5) were increased in the bladder tissues by 48 and 69%, respectively. Moreover, the activities of dimethylnitrosamine N-demethylase I and arylhydrocarbon hydroxylase, ethoxycoumarin O-deethylase, ethoxyresourfin O-deethylase, and pentoxyresorufin O-pentoxyresorufin were increased by 75, 159, 49, 63 and 44%, respectively. The signal intensity for cytochrome P450 2E1 was greatly increased over the control. Also, the activity of glutathione S-transferase was increased by 89%. On the other hand, the activity of glutathione reductase and the level of reduced glutathione were decreased by 40 and 57%, respectively. Interestingly, the level of free radical, thiobarbituric acid reactive substance, was increased in the schistosome-infected human bladder tissues by 125%. The present study clearly demonstrated that S. haematobium changes the activity of carcinogen-metabolizing enzymes. We conclude that S. haematobium could enhance the carcinogenicity of polycyclic aromatic hydrocarbons (e.g. benzo(a)pyrene) and N-nitrosamines (e.g. dimethylnitrosamine) through induction of their corresponding bioactivating enzymes in human bladder tissues.