Carrera G, Alary J, Melgar M J, Lamboeuf Y, Pipy B
Laboratoire de la Signalisation et de la Differenciation des Macrophages, INSERM CJF 91/07, Hopital Rangueil, 31403 Toulouse Cedex, France.
Arch Environ Contam Toxicol. 1998 Jul;35(1):89-96. doi: 10.1007/s002449900354.
The changes in metabolism and cytotoxicity of chlorpropham (CIPC) and its major metabolites, 4-hydroxychlorpropham (4-OH CIPC), 3-chloroaniline, and 3-chloroacetanilide were investigated in isolated rat hepatocyte suspensions after a partial inhibition of sulphation and glucuronidation and the two reactions combined in an attempt to assess the part of each of them in the enhanced CIPC toxicity observed in vivo after D-galactosamine treatment. With sulphation and glucuronidation effective, CIPC has a cytolytic effect and reduces intracellular ATP and K+ level while 4-OH CIPC has a weak cytolytic effect but modifies ATP and K+ level in a greater extent than CIPC. Inhibition of sulphation does not affect the cytotoxicity of CIPC or 4-OH CIPC because there is a compensatory increase in the amount of 4-OH CIPC glucuronide formed and the level of free 4-OH CIPC always remain low. In contrast, when incubations are carried out with either CIPC or 4-OH CIPC, the presence of D-galactosamine leads to a decrease of glucuronide and sulphate conjugates accompanied, respectively, by a 3.6-fold and 6. 9-fold increase of the free 4-OH CIPC level in the culture medium. This alteration of the metabolism is followed by a marked reduction of ATP synthesis with a concomitant modification of cell permeability. The cytolytic effect is due to CIPC itself, whereas the effect on energy supply was attributed to free 4-OH CIPC. The results demonstrate a combined effect of free 4-OH CIPC and D-galactosamine on intracellular ATP level that could account for the partial inhibition of sulphation. This change in the CIPC metabolism could explain the increased CIPC toxicity observed in vivo after D-galactosamine pretreatment.
在部分抑制硫酸化和葡萄糖醛酸化以及二者联合抑制后，研究了氯苯胺灵（CIPC）及其主要代谢产物4-羟基氯苯胺灵（4-OH CIPC）、3-氯苯胺和3-氯乙酰苯胺在分离的大鼠肝细胞悬液中的代谢变化和细胞毒性，以评估它们各自在D-半乳糖胺处理后体内观察到的CIPC毒性增强中所起的作用。当硫酸化和葡萄糖醛酸化有效时，CIPC具有细胞溶解作用并降低细胞内ATP和K⁺水平，而4-OH CIPC具有较弱的细胞溶解作用，但比CIPC在更大程度上改变ATP和K⁺水平。硫酸化的抑制不影响CIPC或4-OH CIPC的细胞毒性，因为形成的4-OH CIPC葡萄糖醛酸苷量有代偿性增加，且游离4-OH CIPC水平始终保持较低。相反，当用CIPC或4-OH CIPC进行孵育时，D-半乳糖胺的存在导致葡萄糖醛酸苷和硫酸酯结合物减少，同时培养基中游离4-OH CIPC水平分别增加3.6倍和6.9倍。这种代谢改变随后伴随着ATP合成的显著减少以及细胞通透性的相应改变。细胞溶解作用归因于CIPC本身，而对能量供应的影响归因于游离4-OH CIPC。结果表明游离4-OH CIPC和D-半乳糖胺对细胞内ATP水平有联合作用，这可能解释了硫酸化的部分抑制。CIPC代谢的这种变化可以解释D-半乳糖胺预处理后体内观察到的CIPC毒性增加。
