Alaoui-Jamali M A, Rossignol G, Castonguay A
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec, Canada.
Carcinogenesis. 1991 Mar;12(3):379-84. doi: 10.1093/carcin/12.3.379.
In this investigation, the effect of vitamin A on 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced genotoxic damage in rat liver was studied and correlated with NNK metabolism and DNA single strand breaks (DNA-SSBs). Male adult Fischer rats were fed a vitamin A deficient diet for 8 weeks and then divided into two sub-groups. Rats in group Ia and group Ib were fed vitamin A supplemented and vitamin A deficient diets respectively for an additional 4 weeks. Rats were then treated with a single i.p. injection of NNK (25-100 mg/kg) and subjected to partial hepatectomy 1 week later. After 72 h, liver perfusions were performed for cell preparation. Non-hepatectomized rats were used as controls (group IIa and IIb, consisting of rats fed vitamin A supplemented and deficient diets respectively). In non-hepatectomized rats (groups IIa and IIb), micronucleus (MN) frequencies were not significantly increased. This confirms the importance of cell proliferation for MN formation. In rats fed a vitamin A deficient diet and subjected to partial hepatectomy (group Ib), a significant increase of MN was observed (2.2 +/- 0.3, 5.7 +/- 0.9, 12.8 +/- 3.8 and 21.2 +/- 4.3% for control, 25, 50 and 100 mg NNK/kg body wt respectively). In rats fed a vitamin A supplemented diet (group Ia) we have observed a significant decrease of MN induction, as compared to rats fed a vitamin A deficient diet (group Ib) (2.7 +/- 1.0, 2.9 +/- 0.9, 9.7 +/- 2.7, 14.8 +/- 3.2% for control, 25, 50 and 100 mg NNK/kg body wt respectively). Freshly isolated hepatocytes from rats fed vitamin A deficient and supplemented diets but without NNK treatment in vivo were used to study NNK metabolism and DNA-SSBs. Results showed that hepatocytes isolated from rats fed a vitamin A supplemented diet (group C) metabolized NNK less effectively than hepatocytes isolated from rats fed a vitamin A deficient diet (group B) (NNK metabolism was decreased by 0.5-fold in group C as compared to group B). This inhibition was observed only with the NNK activation pathway, alpha-carbon hydroxylation, but not with a deactivation pathway: pyridine-N-oxidation. DNA-SSBs induced by NNK were also reduced in hepatocytes isolated from rats fed a vitamin A supplemented diet as compared to hepatocytes isolated from rats fed a deficient diet. These reductions were 7.8, 12.4 and 4.5% after 6 h of elution and 9.1, 8.5 and 3.0% after 9 h of elution for 1, 5 and 10 mM NNK respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
在本研究中，研究了维生素A对4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）诱导的大鼠肝脏遗传毒性损伤的影响，并将其与NNK代谢及DNA单链断裂（DNA-SSB）相关联。成年雄性Fischer大鼠先食用维生素A缺乏饮食8周，然后分为两个亚组。Ia组和Ib组大鼠分别再食用补充维生素A和缺乏维生素A的饮食4周。随后大鼠经腹腔单次注射NNK（25 - 100 mg/kg），并在1周后进行部分肝切除术。72小时后，进行肝脏灌注以制备细胞。未进行肝切除的大鼠用作对照（IIa组和IIb组，分别由食用补充维生素A和缺乏维生素A饮食的大鼠组成）。在未进行肝切除的大鼠（IIa组和IIb组）中，微核（MN）频率未显著增加。这证实了细胞增殖对MN形成的重要性。在食用维生素A缺乏饮食并进行部分肝切除的大鼠（Ib组）中，观察到MN显著增加（对照组、25、50和100 mg NNK/kg体重组的MN分别为2.2±0.3、5.7±0.9、12.8±3.8和21.2±4.3%）。与食用维生素A缺乏饮食的大鼠（Ib组）相比，在食用补充维生素A饮食的大鼠（Ia组）中，我们观察到MN诱导显著降低（对照组、25、50和100 mg NNK/kg体重组的MN分别为2.7±1.0、2.9±0.9、9.7±2.7、14.8±3.2%）。使用在体内未接受NNK处理但分别食用维生素A缺乏和补充饮食的大鼠新鲜分离的肝细胞来研究NNK代谢和DNA-SSB。结果表明，与从食用维生素A缺乏饮食的大鼠分离的肝细胞（B组）相比，从食用补充维生素A饮食的大鼠分离的肝细胞（C组）代谢NNK的效率较低（与B组相比，C组的NNK代谢降低了0.5倍）。仅在NNK激活途径α-碳羟基化中观察到这种抑制，而在失活途径吡啶-N-氧化中未观察到。与从食用缺乏饮食的大鼠分离的肝细胞相比，从食用补充维生素A饮食的大鼠分离的肝细胞中NNK诱导的DNA-SSB也减少。对于1、5和10 mM NNK，洗脱6小时后减少了7.8%、12.4%和4.5%，洗脱9小时后减少了9.1%、8.5%和3.0%。（摘要截断于400字）
Zotero 插件