Center for Environmental Health Sciences, Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762, USA.
Exponent, Alexandria, Virginia 22314, USA.
Toxicol Sci. 2021 Sep 28;183(2):404-414. doi: 10.1093/toxsci/kfab031.
Inhibition kinetics assays were conducted with 16 commercial organophosphate (OP) pesticides or their metabolites on acetylcholinesterase (AChE) in erythrocyte "ghost" preparations from 18 individual humans (both sexes; adults, juveniles, and cord blood samples; mixed races/ethnicities) and pooled samples from adult rats (both sexes). A well-established spectrophotometric assay using acetylthiocholine as substrate and a chromogen was employed. The kinetic parameters bimolecular rate constant (ki), dissociation constant (KI), and phosphorylation constant (kp) were calculated for each compound. As expected, a wide range of potencies were displayed among the tested compounds. Statistical analysis of the resultant data indicated no differences in sex, age, or race/ethnicity among the human samples that are unexpected based on chance (4.2% statistically significant out of 48 parameters calculated) and no differences between the sexes in rats. The bimolecular rate constants for 10 of the compounds were not statistically different between rats and humans. The data indicate that, consistent with the high level of conservation of AChE among species and the fact that AChE at different locations within a species arises from the same gene, the inhibition kinetic parameters calculated from rat erythrocyte ghost preparations should be useful in estimating potencies of OP compounds on target AChE in humans. Additionally, the data indicate that differences in sensitivities among individual humans were not apparent.
抑制动力学分析采用 16 种商业有机磷（OP）农药或其代谢物在来自 18 个人（男女；成人、青少年和脐血样本；混合种族/族裔）和成年大鼠（雌雄）混合样本的红细胞“幽灵”制剂中的乙酰胆碱酯酶（AChE）上进行。采用了一种使用乙酰硫代胆碱作为底物和显色剂的成熟分光光度测定法。为每种化合物计算了双分子速率常数（ki）、离解常数（KI）和磷酸化常数（kp）。正如预期的那样，在测试的化合物中显示出了广泛的效力范围。对所得数据的统计分析表明，在人类样本中，性别、年龄或种族/族裔之间没有意外的差异（48 个计算参数中有 4.2%具有统计学意义），并且大鼠之间的性别没有差异。10 种化合物的双分子速率常数在大鼠和人类之间没有统计学差异。数据表明，与物种间 AChE 的高度保守一致，以及物种内不同位置的 AChE 源自同一基因的事实一致，从大鼠红细胞幽灵制剂中计算出的抑制动力学参数应该有助于估计 OP 化合物对人类靶标 AChE 的效力。此外，数据表明个体人类之间的敏感性差异不明显。
