PubMed · 7035918
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H U Aeschbacher, E Ruch. 1982. Urine-mediated Ames test: interactions.. https://doi.org/10.1016/0165-7992(82)90017-3
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A possible role of oxidative stress in producing acute toxicity in rat liver by aromatic amines and nitroarenes was tested. Oxidative stress was assessed by measuring the excretion of oxidized glutathione (GSSG) into the bile in isolated perfused livers and in female Wistar rats with cannulated bile ducts. The liver perfusion system was calibrated with t-butylhydroperoxide (t-BH) and menadione. The minimal concentration in the perfusate of t-BH necessary to observe a significant effect was 18 microM for 5 min. It was calculated that rat liver is able to cope with an extra production of about 70 nmol GSSG per min and g liver before GSSG is excreted into bile. No effect was observed when 2-aminofluorene, 2-acetylaminofluorene (AAF), trans-4-aminostilbene, and trans-4-acetylaminostilbene were added to the perfusate at 50 microM for 20 min. Moreover, 2-aminofluorene, trans-4-aminostilbene, 2-nitrofluorene and trans-4-nitrostilbene did not increase GSSG excretion when administered simultaneously with effective concentrations of t-BH. AAF was not acutely toxic, blood transaminases and lipid peroxidation were not increased with AAF doses as high as 1 mmol/kg. Since the dose rate of aromatic amines, like AAF, in feeding studies for tumor formation is about 100 times below that examined in the isolated perfused livers, it is highly unlikely that oxidative stress is generated by metabolites able to undergo redox cycling and that reactive oxygen contributes to acute toxic effects.
The abilities of liver cytosol fractions from the suncus and Sprague-Dawley (SD) rats to N-acetylate aniline, p-aminobenzoic acid, p-aminosalicylic acid and 2-aminofluorene (AF) were compared. The cytosol from rats N-acetylated these substrates at efficient rates, whereas the cytosol from the suncus did not N-acetylate these substrates at detectable rates. When AF was given to the suncus, 2-acetylaminofluorene (AAF), a metabolite of AF formed by N-acetyltransferase (NAT), was not detectable in serum, whereas the metabolite was seen clearly in rats. Northern blot and Southern blot analyses, using cDNAs coding for human NATs as probes, indicated that not only the transcripts but also the genes of the enzymes were undetectable in suncus. These results suggest that the suncus is among the few species known to lack NATs.
This study compared the rates of N-deacylations of N-hydroxy-N-2-fluorenylbenzamide (N-OH-2-FBA) with those of its analogue, N-hydroxy-N-2-fluorenylacetamide (N-OH-2-FAA), by the mammary gland (tumor target for both compounds) and the liver of female Sprague-Dawley rats and examined the effect of ovariectomy on these activities. N-Debenzoylation of N-OH-2-FBA was catalyzed by the mammary and liver microsomes of 50-day-old female rats at similar rates (approximately 24 nmol/min/mg). The activity of both tissues increased (up to 1.8 times) after ovariectomy at 42, 32 and, especially, 22 days of age. The rapid hydrolysis appeared to be unique for the benzoyl group since N-OH-2-FAA was deacylated only approximately 0.05 and 0.004 times as fast by the liver and mammary microsomes, respectively, and these low rates were unaffected by ovariectomy. Since such substrate specificity would be of significance in the metabolism of xenobiotics and drug design, esterase activity and its sensitivity to ovariectomy at 22 days of age were examined with several acetylated and benzoylated substrates in the liver and mammary microsomes and compared with those of male liver. Tissues of rats of both sexes had a greater capacity to hydrolyze carboxyl esters than amides. Expect for N-2-fluorenylacetamide (2-FAA) and o-nitrophenylacetate (o-NPA), all substrates were hydrolyzed by liver microsomes of the male up to 3.9 times faster than by those of the female. Microsomes of female liver hydrolyzed acetylated substrates 1.2 to 25 times faster than benzoylated analogues except for N-OH-2-FBA and benzamide. By contrast, mammary gland microsomes hydrolyzed benzoylated compounds 1.4 to 333 times faster except for 2-naphthyl benzoate. Respective rates of hydrolysis of o-NPA by microsomes of liver and mammary gland were 1.7 and 0.6 times those of p-NPA. After ovariectomy, deacylating activities increased (up to 1.6 times) except for those of 2-FAA and acetanilide. All deacylations were > 98% inhibited by 0.1 mM paraoxon, indicating catalysis by serine hydrolases. The results suggest involvement of multiple carboxylesterases and indicate that certain benzoylated xenobiotics may have a greater effect on the mammary gland than acetylated xenobiotics because of their greater vulnerability to hydrolysis by esterases of mammary gland.