Mei-Sie Lee

Glucuronidation of carcinogenic arylamine metabolites by rat liver microsomes.

Since 2-acetylaminofluorene (2-AAF), 4-acetylaminobiphenyl (4-AABP) and 2-aminonaphthalene (2-AN) display varying degrees of carcinogenicity in the rat, which is capable of N-acetylating arylamines, an attempt was made to correlate the difference in carcinogenicity of these compounds with the ease of O-glucuronidation of their hydroxamic acids by rat hepatic microsomes, a reaction believed to be a detoxification mechanism. UDP-glucuronosyltransferase activity of rat hepatic microsomes was activated by Triton X-100. Glucuronidation by Triton X-100 activated microsomes of the N-hydroxy derivative of 2-AN was approximately 1.5 and 1.8 times faster than the corresponding derivatives of 2-aminofluorene (2-AF) and 4-aminobiphenyl (4-ABP) respectively. However, glucuronidation of the N-hydroxy-N-acetyl derivative of 2-AN was 40 and 17 times faster than the corresponding derivatives of 2-AF and 4-ABP respectively. Aroclor 1254 and 3-methylcholanthrene, but not phenobarbital, acetanilide and butylated hydroxytoluene, induced the enzyme for the glucuronidation of 2-AN derivatives. The present study (1) demonstrates an inverse relationship between the carcinogenicity of 2-AN, 4-AABP and 2-AAF and the ease of glucuronidation of their hydroxamic acid derivatives, and (2) suggests that, in addition to N- and C-hydroxylation, glucuronidation may play an important role in determining the carcinogenicity of arylamines and arylacetamides in the rat.

Inhibition by diacylmethane derivatives of mutagenicity in Salmonella typhimurium and tRNA-binding of chemical carcinogens☆

Effects of diacylmethanes on the mutagenicity of 2-naphthohydroxamic acid, methylnitrosourea, benzo[a]pyrene and aflatoxin B1 in S. typhimurium and the tRNA binding by benzo[a]pyrene and aflatoxin B1 were investigated. Acetylacetone, benzoylacetone and dibenzoylmethane inhibited the mutagenicity of 2-naphthohydroxamic acid, and dibenzoylmethane and 1,3-indandione inhibited that of methylnitrosourea, benzo[a]pyrene and aflatoxin B1. The binding to tRNA of benzo[a]pyrene and aflatoxin B1 was inhibited by benzoylacetone and dibenzoylmethane, and dibenzoylmethane, 1,3-indandione and 1,1,1-trifluoroacetylacetone, respectively. The inhibition of methylnitrosourea mutagenicity was observed when the bacteria were exposed concomitantly to the inhibitors and the mutagen, but not when they were exposed to the inhibitors 1 h after exposure to the mutagen. These results demonstrate that active methylene compounds can inhibit mutagenicity and nucleic acid-binding of chemical carcinogens presumably by trapping carcinogenic electrophiles, and they are potential anti-carcinogenic agents during the initiation stage.

O-esters of N-acylhydroxylamines: toxicity and enhancement of sister-chromatid exchange in chinese hamster ovary cells☆

2-Naphthohydroxamic acid, 4-n-butoxyphenylacetohydroxamic acid, and their O-sulfonate, O-formate, O-acetate, and O-propionate derivatives were studied for cytotoxicity and sister chromatid exchange (SCE) induction in Chinese hamster ovary (CHO) cells. 2-Naphthylisocyanate, 2-aminonaphthalene (2 Lossen rearrangement products of the O-sulfonate derivative of 2-naphthohydroxamic acid), and N-methyl-2-naphthohydroxamic acid were also studied. All of these chemicals were cytotoxic and significantly increased SCE frequency, although there was a lack of correlation between these 2 effects. 2-naphthylisocyanate and 2-aminonaphthalene were not as cytotoxic nor as active in inducing SCEs as the O-sulfonate ester of 2-naphthohydroxamic acid suggesting that the cytotoxicity and SCE induction of the latter are not due to its decomposition products.

Mutagenicities of N-acyl-N-arylhydroxylamines for Salmonella.

The N-formyl, N-acetyl and N-propionyl derivatives of N-hydroxy-trans-4-aminostilbene (N-OH-AS), N-hydroxy-4-aminobiphenyl (N-OH-ABP) and N-hydroxy-2-aminonaphthalene (N-OH-AN) were synthesized and examined for their mutagenicities in Salmonella typhimurium TA 98. The N-formyl derivatives were direct-acting mutagens possibly due to hydrolysis, either spontaneously or by bacterial enzymes to hydroxylamines. Their mutagenicities were enhanced by rat liver microsomes and cytosol. All acetyl and propionyl derivatives required activation by either liver cytosol or microsomes. NADPH slightly decreased the microsome-mediated mutagenicities of the N-acyl derivatives of N-OH-AN. However, it greatly enhanced the cytosol-mediated mutagenicities of these hydroxamic acids, probably due to stabilization of their hydroxylamine derivatives. The mutagenicities reported here do not correlate with previously reported carcinogenicity data. Thus, data obtained in Salmonella mutagenicity studies may not necessarily directly reflect carcinogenic potential in mammalian systems due to the different mechanisms of activation.

CARCINOGENECITY OF THE N-ACYL DERIVATIVES OF N-HYDROXY-TRANS-4-AMINOSTILBENE IN CD RATS

Carcinogenicities of the N-formyl (N-OH-FAS), N-acetyl (N-OH-AAS) and N-propionyl (N-OH-PAS) derivatives of N-hydroxy-trans-4-aminostilbene (N-OH-AS) were investigated in male and female CD rats. They were injected, i.p. 10 mumol/kg body weight (bwt) twice a week for 6 weeks, and they were killed at the end of 62 weeks. The N-formyl, N-acetyl and N-propionyl derivatives of N-hydroxy-4-aminobiphenyl (N-OH-ABP) were similarly injected at a dose of 100 mumol/kg bwt for comparison in female CD rats. Tumors of the liver, mammary gland and ear duct were produced in the female rats by these N-OH-AS derivatives. N-OH-AAS and N-OH-PAS were more active in the induction of mammary and ear duct tumors than N-OH-FAS. These N-OH-AS derivatives produced more tumors than did the N-OH-ABP derivatives, even at 1/10 dose of the N-OH-ABP derivatives. In male CD rats, these N-OH-AS derivatives produced peritesticular mesothelioma and tumors of the pancreas and ear duct. N-OH-PAS also produced tumors of the small intestine and lung. The acetyl and propionyl derivatives were more carcinogenic than the formyl derivative of N-OH-AS for both male and female CD rats, suggesting that cytosolic acetyltransferases may be more important than the microsomal ones in activating these carcinogens.