Neonatal ontogeny of murine arylamine N-acetyltransferases:: Implications for arylamine genotoxicity
Neonatal ontogeny of murine arylamine N-acetyltransferases:: Implications for arylamine genotoxicity
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DOI：
10.1093/toxsci/kfg086
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发表时间：
2003-06-01
影响因子：
3.8
通讯作者：
Chau, B
中科院分区：
文献类型：
--
作者：
McQueen, CA;Chau, B
异生素生物转化酶表达中与生物素相关的变化可导致化学活化和解毒速率的差异，影响对化学品的治疗和/或毒性作用的反应。尽管认识到儿童和成人对化学品的敏感性可能存在差异，但有关发育中特定生物转化酶何时表达的信息尚不完整。N-乙酰基转移酶（NATs）是催化芳胺和肼致癌物和治疗药物的乙酰化的II相酶。在C57 B1/6小鼠中研究出生后NAT 1和NAT 2的表达。肝脏NAT 1和NAT 2信使RNA（mRNA）随着年龄的增加，从新生儿（ND）4天，以非线性的方式成人。通过测量NAT活性与异构体选择性底物对氨基苯甲酸和异烟肼，以及致癌物2-氨基芴和4-氨基联苯（4ABP）的功能蛋白质的存在得到证实。新生儿肝脏能够乙酰化所有的底物，随着年龄的增长，活动增加。CYP 1A 2（另一种参与芳胺生物转化的酶）的蛋白表达也显示出类似的模式。通过测定肝脏4ABP-DNA加合物来评估4ABP的遗传毒性。在新生儿期，4ABP-DNA加合物呈年龄依赖性增加。因此，新生儿中NAT 1和NAT 2基因表达的发育增加与4ABP遗传毒性降低相关。在小鼠中的生物转化酶的表达与年龄相关的模式是一致的，与人类的数据NAT，并表明这可能发挥作用的发展差异芳胺毒性。
Age-related changes in the expression of xenobiotic biotransformation enzymes can result in differences in the rates of chemical activation and detoxification, affecting responses to the therapeutic and/or toxic effects of chemicals. Despite recognition that children and adults may exhibit differences in susceptibility to chemicals, information about when in development specific biotransformation enzymes are expressed is incomplete. N-acetyltransferases (NATs) are phase II enzymes that catalyze the acetylation of arylamine and hydrazine carcinogens and therapeutic drugs. The postnatal expression of NAT1 and NAT2 was investigated in C57Bl/6 mice. Hepatic NAT1 and NAT2 messenger RNAs (mRNAs) increased with age from neonatal day (ND) 4 to adult in a nonlinear fashion. The presence of functional proteins was confirmed by measuring NAT activities with the isoform selective substrates p-aminobenzoic acid and isoniazid, as well as the carcinogens 2-aminofluorene and 4-aminobiphenyl (4ABP). Neonatal liver was able to acetylate all of the substrates, with activities increasing with age. Protein expression of CYP1A2, another enzyme involved in the biotransformation of arylamines, showed a similar pattern. The genotoxicity of 4ABP was assessed by determining hepatic 4ABP-DNA adducts. There was an age-dependent increase in 4ABP-DNA adducts during the neonatal period. Thus, developmental increases in expression of NAT1 and NAT2 genes in neonates are associated with less 4ABP genotoxicity. The age-related pattern of expression of biotransformation enzymes in mice is consistent with human data for NATs and suggests that this may play a role in developmental differences in arylamine toxicity.