Moody D E, Clawson G A, Piper W N, Smuckler E A
Toxicol Appl Pharmacol. 1984 Sep 30;75(3):561-70. doi: 10.1016/0041-008x(84)90193-5.
Previous studies showed that 1,2-dibromo-3-chloropropane (DBCP) caused a decrease in hepatic microsomal cytochrome P-450 [D.E. Moody, B. Head, and E.A. Smuckler (1979) J. Environ. Pathol. Toxicol. 3, 177-190; D.E. Moody, G.A. Clawson, C.H. Woo, and E.A. Smuckler (1982) Toxicol. Appl. Pharmacol. 66, 278-279], suggesting that hepatic heme metabolism may be affected by DBCP treatment. This study tested this hypothesis. Various parameters of hepatic heme synthesis were measured at intervals ranging from 0 to 72 hr in male Sprague-Dawley rats given a single oral dose (200 mg/kg) of DBCP. Incorporation of the radiolabeled heme precursor [delta-14C]aminolevulinic acid (14C-ALA) into liver, protein, extracted heme, and subcellular fractions of liver homogenates was significantly decreased to 75, 58, and 81% of controls, respectively, at 24 hr. At 48 and 72 hr after DBCP treatment, the accumulation of 14C-ALA label after 4 hr in liver homogenates and subcellular fractions was significantly increased in comparison to controls. These changes in 14C-ALA uptake were accompanied by decreases in total liver and microsomal heme, but not mitochondrial heme. Decreases were found in the spectral content of two heme proteins, cytochromes P-450 and b5, and the activity of another heme protein, catalase. Heme oxygenase activity increased to 130, 151, 209, and 186% of control values at 12, 24, 48, and 72 hr after DBCP, respectively. A slight, but significant, increase in ALA-synthetase to 112% of controls occurred at 24 hr, and slight, but significant, decreases in ALA-dehydratase to 90 and 80% of control occurred at 12 and 24 hr, respectively. No significant changes in uroporphyrinogen-1-synthetase or ferrochelatase at the time points tested was noted. The porphyrin content of liver was increased to 130% of control, while the serum and urine porphyrin levels were decreased to 30% of the control values at 24 hr. Liver ALA content was not significantly altered through the time period studied, but serum and urine levels were increased at 24 hr to 176 and 130% of the control values, respectively. In conclusion, the decreases in liver heme proteins following a single oral dose of DBCP are accompanied by alterations in heme turnover, particularly a prolonged increase in heme oxygenase activity.
先前的研究表明，1,2 - 二溴 - 3 - 氯丙烷（DBCP）会导致肝脏微粒体细胞色素P - 450减少[D.E.穆迪、B.黑德和E.A.斯马特勒（1979年）《环境病理学与毒理学杂志》3, 177 - 190；D.E.穆迪、G.A.克劳森、C.H.吴和E.A.斯马特勒（1982年）《毒理学与应用药理学》66, 278 - 279]，这表明DBCP处理可能会影响肝脏血红素代谢。本研究对这一假设进行了验证。在给予单次口服剂量（200毫克/千克）DBCP的雄性斯普拉格 - 道利大鼠中，于0至72小时的不同时间间隔测量肝脏血红素合成的各种参数。在24小时时，放射性标记的血红素前体[δ - 14C]氨基乙酰丙酸（14C - ALA）掺入肝脏、蛋白质、提取的血红素以及肝脏匀浆亚细胞组分中的量分别显著降至对照组的75%、58%和81%。在DBCP处理后48小时和72小时，与对照组相比，肝脏匀浆和亚细胞组分在4小时后14C - ALA标记的积累显著增加。14C - ALA摄取的这些变化伴随着肝脏和微粒体总血红素的减少，但线粒体血红素未减少。发现两种血红素蛋白细胞色素P - 450和b5的光谱含量以及另一种血红素蛋白过氧化氢酶的活性降低。血红素加氧酶活性在DBCP处理后12、24、48和72小时分别增加至对照值的130%、151%、209%和186%。在24小时时，ALA合成酶轻微但显著增加至对照组的112%，在12小时和24小时时，ALA脱水酶分别轻微但显著降至对照组的90%和80%。在所测试的时间点，未观察到尿卟啉原 - 1 - 合成酶或亚铁螯合酶有显著变化。肝脏卟啉含量增加至对照的130%，而在24小时时，血清和尿液卟啉水平降至对照值的30%。在所研究的时间段内，肝脏ALA含量未显著改变，但在24小时时，血清和尿液水平分别增加至对照值的176%和130%。总之，单次口服DBCP后肝脏血红素蛋白的减少伴随着血红素周转的改变，特别是血红素加氧酶活性的持续增加。
