Bladder tumor formation

It is of more than a little interest to note that the sites of tumor formation do not always match across species. Benzidine, a substance once widely used in dye manufacture, was shown many years ago to be a carcinogenic risk for the bladder in workers exposed to excessive levels. The rat bladder is not responsive to this substance, but its liver is. It wasn t until Wilhelm Hueper turned to the dog that bladder cancer could be reproduced in a laboratory animal. It is now understood that benzidine metabolism is similar in dogs and people, and that metabolism in the rat takes a different course. It is also understood that certain benzidine metabolites, and not benzidine itself, are the proximate causes of tumors. Knowledge of metabolic differences helps explain the species similarities and differences in tumor response. If we had available the rat data and no human data, we would be in error to conclude that benzidine was a cause of human liver cancer. 

Xylitol is as sweet as sucrose and has been used as a food additive. Because it does not induce formation of dental plaque, it is used as a replacement for sucrose in chewing gum. It appeared to be an ideal sugar substitute for diabetics. However, despite the fact that it is already naturally present in the body, ingestion of large amounts of xylitol causes bladder tumors as well as oxalate stones in rats and mice. Its use has, therefore, been largely discontinued. A possible source of the problem may lie in the conversion by fructokinase of some of the xylitol to D-xylulose 1 -P, which can be cleaved by the xylulose 1-P aldolase to dihydroxy acetone P and glycolaldehyde. 

The A-glucuronides of the A -hydroxyarylamines are transported to the bladder, where, upon hydrolysis by [i-glucuronidase and in the presence of acidic urine, N-hydroxylarylamines are formed. Spontaneously, the electrophilic arylnitrenium ion forms, which can then react with nucleophilic centers of the epithelium in the bladder to initiate tumor formation. 

Methemoglobin formation was considered the most serious health outcome following exposure to 2NA until the increased rate of urinary bladder tumors were confirmed in the workers. Methemoglobinemia is symptom-less until acutely toxic. In one report workers exposed to 2NA were required to pass through the medical department following their shift so that any cyanosis could be ascertained. 

Mention is made that vitamin C seems to be effective against bladder cancer, with studies cited. An interesting example is furnished of petrochemical plant workers whose urine would give off light, the phenomenon of chemiluminescence, and which was indicative of bladder cancer. Vitamin C countered this, presumably by preventing the formation of cinnabarinic acid, which is associated with tumor formation. 

In a comparison experiment, the possibility that vitamin C and P-carotene could affect PhIP-DNA adduct formation has been examined. Previous reports have already demonstrated the protective role of vitamin C in certain types of cancer and low intake of foods rich in vitamin C is associated with an increased risk of gastric cancer [100]. Vitamin C prevents DNA adduct formation in mice treated with the mycotoxins ochratoxin A and zearalenone [101]. Wu et al. [102] reported that vitamin C inhibited aiylamine N-acetyltransferase (NAT) activity in human bladder tumor cells. This is one possible mechanism by which vitamin C can attenuate the formation of DNA adducts. It... 

Wu HC, Lu HF, Hung CF, Chung JG. Inhibition by vitamin C of DNA adduct formation and arylamine N-acetyltransferase activity in human bladder tumor cells. Urol Res 2000 28 235-240. 

Figure 7. Role of metabolism and sys temic transport in the formation of bladder tumors by 2-naphthylamine...

Pipkin, G. E., 1969, Inhibitory effect of L-ascorbate on tumor formation in urinary bladders implanted with 3-hydroxyanthranilic acid, Proc. Soc. Exp. Biol. Med. 131 522-524. 

Acetamidofluorene (26), which was initially intended to be used as an insecticide178, is one of the most extensively studied chemical carcinogens. This aromatic amide as well as its amine and nitro derivatives induce tumors in a wide variety of sites, including liver, urinary bladder, mammary gland, intestine and forestomach. The initial activation involves the formation of 7V-hydroxy intermediates179,180. 

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