Sulfotransferases, carcinogens

The role of N-sulfonyloxy arylamines as ultimate carcinogens appears to be limited. For N-hydroxy-2-naphthylamine, conversion by rat hepatic sulfotransferase to a N-sulfonyloxy metabolite results primarily in decomposition to 2-amino-l-naphthol and 1-sulfonyloxy-2-naphthylamine which are also major urinary metabolites and reaction with added nucleophiles is very low, which suggests an overall detoxification process (9,17). However, for 4-aminoazobenzene and N-hydroxy-AAF, which are potent hepatocarcinogens in the newborn mouse, evidence has been presented that strongly implicates their N-sulfonyloxy arylamine esters as ultimate hepatocarcinogens in this species (10,104). This includes the inhibition of arylamine-DNA adduct formation and tumorigenesis by the sulfotransferase inhibitor pentachlorophenol, the reduced tumor incidence in brachymorphic mice that are deficient in PAPS biosynthesis (10,115), and the relatively low O-acetyltransferase activity of mouse liver for N-hydroxy-4-aminoazobenzene and N-OH-AF (7,114,115). 

Although several N-methyl-substituted arylamines have been shown to be carcinogenic (184-186), metabolic activation pathways have been investigated primarily for the hepatocarcinogenic aminoazo dyes, N-methyl-4-aminoazobenzene (MAB) and its 3 -methyl derivative (9,21, 22,187,188). N-Hydroxy-N-methyl arylamines are generally regarded as proximate carcinogenic metabolites (22,187,189) and have been shown to be converted to electrophilic N-sulfonyloxy derivatives by hepatic sulfotransferases (9,187) or to reactive N-arylnitrones by air oxidation (21). 

Watabe, T, Hiratsuka, A Ogura, K., and Endoh, K. (1985). A Reactive Hydroxymethyl Sulfate Ester Formed Regioselectively from the Carcinogen 7,12-Dthydroxymethyl benz [a]Anthracene, by Rat Liver Sulfotransferase, Bio-chem. Bio ys. Res. Cammun., 131 694-702,... 

An alternative mechanism for the esterification of V-OH-AAF is the conversion of 4 to 6, as shown in Fig. 1. 31). The formation of A-acetoxy-AAF can occur by a one-electron oxidation process (Fig. 2). This reaction is catalyzed by various peroxidases (29, 31). In addition to the formation of A-acetoxy-AAF, the potential for the formation of the electrophilic sulfate esters of A-OH-AAF was also studied in vitro. It was demonstrated that 3 -phosphoadenosine-5 -phosphosulfate (PAPS) in the presence of rat liver cytosol catalyzed the formation of the sulfate ester of A-OH-AAF. With the exception of the rabbit, the presence of sulfotransferase activity correlated with the susceptibility of the liver of the various species shown in Table V to the carcinogenic activity of N-OH-AAF. 

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