Rankin G O, Shih H C, Yang D J, Richmond C D, Teets V J, Brown P I
Department of Pharmacology, Marshall University School of Medicine, Huntington, West Virginia 25704-2901.
Toxicol Appl Pharmacol. 1988 Dec;96(3):405-16. doi: 10.1016/0041-008x(88)90001-4.
The experimental fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) has been shown to produce selective nephrotoxicity at least in part through the actions of one or more metabolites. The purpose of this study was to (1) determine the nephrotoxic potential of three known NDPS metabolites; N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS), N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (NDHSA), and N-(3,5-dichlorophenyl)malonamic acid (DMA) and (2) examine the role of renal biotransformation in NDPS-induced nephrotoxicity. In one set of experiments, male Fischer 344 rats were administered a single intraperitoneal (ip) injection of NDPS or a NDPS metabolite (0.2, 0.4, or 1.0 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg) and renal function was monitored at 24 and 48 hr. Both NDHS and NDHSA administration (0.2 or 0.4 mmol/kg) resulted in nephrotoxicity similar to that produced by NDPS (0.4 or 1.0 mmol/kg). DMA administration resulted in only minor renal effects. Addition of NDPS to renal cortical slices prepared from naive Fischer 344 rats resulted in decreases in p-aminohippurate (PAH) and tetraethylammonium (TEA) accumulation at NDPS media concentrations of 10(-4) and 10(-5) M or greater, respectively. Pretreatment of rats with microsomal enzyme activity modifiers (phenobarbital, 3-methylcholanthrene, cobalt chloride, or piperonyl butoxide) had little effect on in vitro effects of NDPS on PAH or TEA accumulation. A pattern of PAH or TEA uptake similar to that observed for NDPS was observed in vitro with NDPS-d4, a nonnephrotoxic analog of NDPS labeled on the succinimide ring with deuterium. Of the NDPS metabolites tested in vitro for nephrotoxicity, only NDHS produced decreases in PAH and TEA accumulation similar to those produced by NDPS. These results suggest that the NDPS metabolites NDHS and NDHSA are nephrotoxic compounds. However, the role of these metabolites in NDPS-induced nephrotoxicity remains to be determined. In addition, it appears that NDPS has direct effects on renal function, but these effects do not appear to be of major toxicological significance in vivo. Direct renal bioactivation of NDPS or its known metabolites to nephrotoxic species does not appear to occur in vitro.
实验性杀菌剂N-(3,5-二氯苯基)琥珀酰亚胺(NDPS)已被证明至少部分通过一种或多种代谢物的作用产生选择性肾毒性。本研究的目的是：(1)确定三种已知的NDPS代谢物的肾毒性潜力；N-(3,5-二氯苯基)-2-羟基琥珀酰亚胺(NDHS)、N-(3,5-二氯苯基)-2-羟基琥珀酰胺酸(NDHSA)和N-(3,5-二氯苯基)丙二酸(DMA)；(2)研究肾脏生物转化在NDPS诱导的肾毒性中的作用。在一组实验中，给雄性Fischer 344大鼠单次腹腔注射NDPS或一种NDPS代谢物(0.2、0.4或1.0 mmol/kg)或溶剂(芝麻油，2.5 ml/kg)，并在24小时和48小时监测肾功能。给予NDHS和NDHSA(0.2或0.4 mmol/kg)均导致与NDPS(0.4或1.0 mmol/kg)产生的肾毒性相似。给予DMA仅产生轻微的肾脏影响。将NDPS添加到从未处理的Fischer 344大鼠制备的肾皮质切片中，当NDPS培养基浓度分别为10(-4)和10(-5)M或更高时，对氨基马尿酸(PAH)和四乙铵(TEA)的积累减少。用微粒体酶活性调节剂(苯巴比妥、3-甲基胆蒽、氯化钴或胡椒基丁醚)预处理大鼠对NDPS对PAH或TEA积累的体外作用影响很小。在体外，用NDPS-d4(一种在琥珀酰亚胺环上用氘标记的NDPS非肾毒性类似物)观察到与NDPS相似的PAH或TEA摄取模式。在体外测试肾毒性的NDPS代谢物中，只有NDHS导致PAH和TEA积累减少，与NDPS产生的减少相似。这些结果表明，NDPS代谢物NDHS和NDHSA是肾毒性化合物。然而，这些代谢物在NDPS诱导的肾毒性中的作用仍有待确定。此外，似乎NDPS对肾功能有直接影响，但这些影响在体内似乎没有重大毒理学意义。NDPS或其已知代谢物在体外似乎不会直接肾生物活化成肾毒性物质。
