The biochemistry of aromatic amines. 2. The conversion of arylamines into arylsulphamic acids and arylamine-N-glucosiduronic acids

Abstract

Aromatic amines are known to be metabolized by conversion into acetamido derivatives and oxidation to aminophenols. The aminophenols may be conjugated or further metabolized. In studying the metabolism of 2-naphthylamine by paper chromatography two products were detected which gave the free amine on acidification (Boyland & Manson, 1955). One of these substances could be prepared by treating 2-naphthylamine with sodium glucuronate in aqueous solution and is presumably sodium 2-naphthylamine N-glucosiduronate. The other product was found to be 2-naphthylsulphamic acid; this product appears to be produced in greater amounts by rabbits than by rats and an analogous reaction occurs with aniline and 1-naphthylamine. Aliphatic sulphamate or N-sulphonate groups are probably present in naturally occurring polysaccharides such as heparin (Reinert & Winterstein, 1939). 2-Naphthylamine and other aromatie amines may be excreted as the N-glucosiduronic acids and as the N-sulphonic acids or sulphamates. EXPERIMENTAL Methods Animals were kept in metabolism cages and the urine was collected daily. Rabbits (approx. 2-5 kg.) and guinea pigs (approx. 400 g.) were fed on cabbage, bran, rat cake and water, rats (approx. 200 g.) on rat cake, bread and water, and hamsters (approx. 85 g.) on rat cake, mash, mixed seeds and water. Amines were injected intraperitoneally in arachis oil. Rabbits were given 0 3 g. of aniline, 4-aminodiphenyl, 1-naphthylamine or 0-5 g. of 2-naphthylamine in 10 ml. of oil; rats received 0-03 g. of each of the first three amines and 0-05 g. of 2-naphthylamine in 1 ml. of oil; guinea pigs received 0-06 g. of 2-naphthylamine in 1-5 ml. of oil; hamsters received 0-02 g. of 2-naphthylamine in 0-5 ml. of oil. Paper chromatography. Upward and downward development was employed with Whatman no. 1 chromatography paper. Solvent systems used were (a) n-butanol-propan-lol-0-1w-NH3 soln.

The Biliary Excretion and Enterohepatic Circulation of Drugs and Other Organic Compounds

“…Sulphate conjugation is commonly associated with phenols but it has also been shown to occur with aliphatic alcohols [35,36] and with aromatic amines [37,38]. Ethereal sulphate formation is widely distributed and is believed tobe the most primitive of the detoxication mechanisms.…”

The induction of rat bladder cancer by 2-naphthylamine

“…It had been recognized very early that 2-naphthylamine per se was not carcinogenic after implantation into the bladder of 8 mice (Bonser et al, 1952) and instillation of 2-naphthylamine into the bladder of one dog (Bonser et al, 1954). Boyland and his colleagues (Boyland et al, 1957) suggested the active urinary pre-carcinogen might be 2 -amino -1 -napthylglucuronide which, when hydrolysed in urine by P-glucuronidase, could release 3,2-amino-i -naphthol, which they postulated was the ultimate reactive carcinogen. This suggestion was discounted at the time, partly because both 2-amino-i-naphthylglucuronide and /-glucuronidase were present in rat urine, yet, as everyone knew, rats "do not develop bladder cancer when dosed with 2-naphthylamine" (Deichmann & Radomski, 1963).…”

The Metabolism of 5-p-Aminobenzenesulphonamido-3-Methylisothiazole (Sulphasomizole)

“…The occurrence of an aryl sulphamate (N4-sulphosulphasomizole, IV) was suspected in rat and dog urine and these compounds (aryl sulphamates) are known metabolites of some aromatic amines in vivo (Boyland, Manson and Orr, 1957;Parke, 1960) and in vitro (Roy, 1960;1961). There are also reports in the Japanese literature of the occurrence in urine of the sulphamates of sulphathiazole (Uno and Veda, 1960), sulphisoxazole (Uno and Kono, 1960), and sulfamethylthiadiazole (Uno and Okazaki, 1960).…”