Identification of hepatic mitogenic and cytochrome P-450-inducing fractions of unleaded gasoline in B6C3F1 mice.
Identification of hepatic mitogenic and cytochrome P-450-inducing fractions of unleaded gasoline in B6C3F1 mice.
复制标题
B6C3F1 小鼠中无铅汽油的肝有丝分裂和细胞色素 P-450 诱导组分的鉴定。
DOI：
10.1080/15287399409531916
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Goldsworthy,TL
中科院分区：
文献类型：
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作者：
Standeven,AM;Goldsworthy,TL
无铅汽油 (UG) 是 300 多种碳氢化合物的复杂混合物，可选择性诱导雌性小鼠发生肝肿瘤，并表现出促进肝肿瘤的活性。 UG 还诱导小鼠肝脏中的细胞增殖和细胞色素 P-450 相关酶活性，这些特性通常与肝脏肿瘤促进剂相关。为了确定 UG 的促有丝分裂和/或细胞色素 P-450 诱导特性是否存在于 UG 的各个级分中，根据沸点 (BP) 将 UG 分为四个级分：级分 1，BP < 66°C；级分 1，BP < 66°C；分数 2，66°C < BP < 100°C；分数 3，100°C < BP < 132°C；分数 4，BP > 132°C。组分 1 和 2 合并形成“轻 UG”（BP < 100°C），组分 3 和 4 合并形成“重 UG”（BP > 100°C）。雌性 B6C3F1 小鼠在第 1 天植入含有 5-溴-2'-脱氧尿苷 (BrdU) 的渗透泵，在第 2-4 天通过胃插管用玉米油或 3000 mg/kg/d 轻、重或全 UG 治疗，并在第 5 天安乐死。戊氧基试卤灵 O-脱烷基酶 (PROD) 和乙氧基试卤灵测定肝微粒体中的 O-脱乙基酶 (EROD) 活性，并测定肝切片中的肝细胞 BrdU 标记指数 (LI)。全 UG 和重 UG 引起肝脏 PROD 和 EROD 活性以及肝细胞 LI 的类似增加。轻度UG引起肝脏PROD和EROD活性相对较小的增加，并且不增加肝细胞LI。当在上述治疗方案中分别测试级分3和4时，两个级分均强烈诱导肝脏PROD活性并弱诱导肝脏EROD活性。然而，只有部分 3 增加了肝细胞 LI。为了分离部分3中的促有丝分裂成分，在上述处理方案中测试了部分3中等摩尔剂量的各个化学物质。甲苯不会增加肝细胞LI，而2,2,3-三甲基戊烷(TMP)、2,2,4-TMP和2,3,4-TMP均显着增加肝细胞LI。因此，虽然 UG 的肝细胞色素 P-450 诱导活性集中在 BP > 100°C 的 UG 组分中，但这种活性显然存在于具有广泛 BP 的 UG 组分中。相比之下，UG 的促有丝分裂活性高度集中在 BP 范围为 ~100 至 132°C 的 UG 成分中，并且很可能在特定的 TMP 中。
Unleaded gasoline (UG), a complex mixture of over 300 hydrocarbons, induced liver tumors selectively in female mice and exhibited liver tumor promoting activity. UG also induced cell proliferation and cytochrome P‐450‐related enzyme activities in mouse liver, properties commonly associated with liver tumor promoters. To determine if the mitogenic and/or cytochrome P‐450‐inducing properties of UG reside in individual fractions of UG, UG was separated into four fractions on the basis of boiling point (BP): fraction 1, BP < 66°C; fraction 2, 66°C < BP < 100°C; fraction 3, 100°C < BP < 132°C; fraction 4, BP > 132°C. Fractions 1 and 2 were combined to form “light UG” (BP < 100°C), and fractions 3 and 4 were combined to form “heavy UG” (BP > 100°C). Female B6C3F1 mice were implanted with osmotic pumps containing 5‐bromo‐2'‐deoxyuridine (BrdU) on d 1, treated by intragastric intubation with corn oil or 3000 mg/kg/d of light, heavy, or whole UG on d 2–4, and euthanized on d 5. Pentoxyresorufin O‐dealkylase (PROD) and ethoxyresorufin O‐deethylase (EROD) activities were assayed in hepatic microsomes, and hepatocyte BrdU labeling index (LI) was determined in liver sections. Whole UG and heavy UG caused comparable increases in hepatic PROD and EROD activities and the hepatocyte LI. Light UG caused relatively small increases in hepatic PROD and EROD activities and did not increase the hepatocyte LI. When fractions 3 and 4 were tested separately in the above treatment protocol, both fractions strongly induced hepatic PROD and weakly induced hepatic EROD activities. However, only fraction 3 increased the hepatocyte LI. To isolate mitogenic components in fraction 3, equimolar doses of individual chemicals in fraction 3 were tested in the above treatment protocol. Toluene did not increase the hepatocyte LI, whereas 2,2,3‐trimethylpentane (TMP), 2,2,4‐TMP, and 2,3,4‐TMP all dramatically increased the hepatocyte LI. Thus, while the hepatic cytochrome P‐450‐inducing activity of UG was concentrated in components of UG with BPs > 100°C, this activity apparently resides in UG components with a wide range of BPs. The mitogenic activity of UG, in contrast, was highly concentrated in components of UG with BPs ranging from ∼100 to 132°C, and quite possibly in specific TMPs.