INVITRO EFFECTS OF N-ACETYLCYSTEINE ON THE MUTAGENICITY OF DIRECT-ACTING COMPOUNDS AND PROCARCINOGENS
INVITRO EFFECTS OF N-ACETYLCYSTEINE ON THE MUTAGENICITY OF DIRECT-ACTING COMPOUNDS AND PROCARCINOGENS
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DOI：
10.1093/carcin/5.4.505
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发表时间：
1984-01-01
期刊：
影响因子：
4.7
通讯作者：
DEFLORA, A
中科院分区：
文献类型：
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作者：
DEFLORA, S;BENNICELLI, C;DEFLORA, A
N-乙酰半胱氨酸（NAC）、还原型谷胱甘肽（GSH）和氧化型谷胱甘肽（GSSG）在7株沙门氏菌的艾姆斯试验中均为阴性，而L-半胱氨酸则被大鼠肝S-9组分激活，生成对菌株TA 102、TA 97和TA 100具有致突变性的代谢产物。在体外预孵育NAC与四种直接作用诱变剂和六种前致癌剂后，研究了鼠伤寒沙门氏菌菌株（TA 1535、TA 98、TA 100、TA 102）的诱变反应和酶活性水平，这些酶负责大鼠肝S-9组分中NADP+或GSSG的还原以及NADPH或GSH的利用。用这种亲核性和还原性化合物处理导致表氯醇、过氧化氢和4-硝基喹啉-N-氧化物和重铬酸钠的直接致突变性呈剂量相关性降低。在不存在和存在NAC的情况下，这些化合物的致突变性均被大鼠肝脏S-9组分降低，并在一定程度上被肺S-9组分降低。在前致癌物（环磷酰胺、2-氨基芴、香烟烟雾冷凝物、Trp-P-2、黄曲霉毒素B1和苯并[a]芘）的情况下观察到双相效应，即，在中等NAC剂量下，S-9需要致突变性增强，这可归因于体外作用的代谢因子，而在高NAC剂量下，致突变性丧失，这可归因于亲电代谢物的捕获。在所研究的五种S-9酶活性中，即，葡萄糖-6-磷酸脱氢酶、6-磷酸葡萄糖酸脱氢酶、苹果酸酶、GSH过氧化物酶和GSSG还原酶，只有后者在诱变剂和/或NAC处理后显示出显著变化。
N-Acetylcysteine (NAC), reduced (GSH) and oxidized (GSSG) glutathione were negative in the Ames test with 7Salmonellastrains, while L-cysteine was activated by rat liver S-9 fractions to metabolites mutagenic to strains TA102, TA97 and TA100. The mutagenic response inS. typhimuriumstrains (TA1535, TA98, TA100, TA102) and the levels of enzyme activities, responsible for NADP+ or GSSG reduction and for the utilization of NADPH or GSH in rat liver S-9 fractions, were investigated followingin vitropreincubation of NAC with four direct-acting mutagens and six procarcinogens. Treatment with this nucleophilic and reducing compound resulted in a dose-related decrease of the direct mutagenicity of epichlorohydrin, hydrogen peroxide and, sharply, of 4-nitroquinolino-N-oxide and sodium dichromate. The mutagenicity of these compounds, both in the absence and in the presence of NAC, was decreased by rat liver S-9 fractions and to some extent by lung S-9 fractions. A diphasic effect was observed in the case of procarcinogens (cyclophosphamide, 2-aminofluorene, cigarette smoke condensate, Trp-P-2, aflatoxin B1and benzo[a]pyrene), i.e., an enhancement of S-9 requiring mutagenicity at intermediate NAC doses, which could be ascribed to metabolic factors actingin vitro, and a loss of mutagenicity at high NAC doses, which could be ascribed to trapping of electrophilic metabolites. Out of the five S-9 enzyme activities under study, i.e., glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, malic enzyme, GSH peroxidase and GSSG reductase, only the last one showed significant changes following mutagen and/or NAC treatment.