Cottrell R C, Blowers S D, Walters D G, Lake B G, Purchase R, Phillips J C, Gangolli S D
Carcinogenesis. 1983;4(3):311-4. doi: 10.1093/carcin/4.3.311.
The metabolism of N-nitrosopyrrolidine (NPYR) to 4-hydroxybutanal (4-HB) (the first stable product of the putative alpha-hydroxylation pathway) and its bioactivation in the Ames bacterial mutagenicity test system were examined in the presence of a number of inhibitors. Both SKF 525A and piperonyl butoxide were found to be potent inhibitors of the production of 4-HB by rat liver microsomal preparations but were ineffective in the mutagenicity model with liver S-9 from either untreated or Aroclor 1254 pretreated rats. In addition two inhibitors of the mutagenic activity of N-nitrosodimethylamine (NDMA) in this system, 2-phenylethylamine and benzimidazole failed to reduce the activity of NPYR. These results suggest that the bioactivation of NPYR may proceed by processes other than the cytochrome P-450 dependent route generating 4-HB and the amine oxidase catalysed route implicated in NDMA activation. Evidence was also obtained of a second cytosol dependent bioactivation step involving a microsome generated pre-mutagen. This activity may be responsible, at least in part, for the enhancement by cytosol of the mutagen producing activity of liver microsomes from Aroclor 1254 pretreated (but not control) rats.
在多种抑制剂存在的情况下，研究了N-亚硝基吡咯烷（NPYR）代谢生成4-羟基丁醛（4-HB）（假定的α-羟基化途径的首个稳定产物）的过程及其在Ames细菌致突变试验系统中的生物活化作用。发现SKF 525A和胡椒基丁醚都是大鼠肝微粒体制剂生成4-HB的有效抑制剂，但在使用未处理或经Aroclor 1254预处理大鼠的肝S-9的致突变模型中无效。此外，该系统中两种N-亚硝基二甲胺（NDMA）诱变活性的抑制剂，2-苯乙胺和苯并咪唑，未能降低NPYR的活性。这些结果表明，NPYR的生物活化可能通过生成4-HB的细胞色素P-450依赖性途径和与NDMA活化有关的胺氧化酶催化途径以外的其他过程进行。还获得了涉及微粒体生成的前诱变剂的第二个胞质溶胶依赖性生物活化步骤的证据。这种活性可能至少部分地导致胞质溶胶增强了经Aroclor 1254预处理（而非对照）大鼠肝微粒体的诱变活性。
