Poet T S, Wu H, Kousba A A, Timchalk C
Battelle, Pacific Northwest Division, Chemical Dosimetry, P.O. Box 999, Richland, Washington 99352, USA.
Toxicol Sci. 2003 Apr;72(2):193-200. doi: 10.1093/toxsci/kfg035. Epub 2003 Mar 7.
Chlorpyrifos (CPF) and diazinon (DZN) are thionophosphorus organophosphate (OP) insecticides; their toxicity is mediated through CYP metabolism to CPF-oxon and DZN-oxon, respectively. Conversely, CYPs also detoxify these OPs to trichloropyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), respectively. In addition, A-esterase (PON1) metabolism of CPF- and DZN-oxon also forms TCP and IMHP. This study evaluated the role intestinal and hepatic metabolism may play in both the activation and detoxification of CPF and DZN in Sprague-Dawley rats. Similar CYP- and PON1-mediated metabolic profiles were demonstrated in microsomes from liver or isolated intestinal enterocytes. The metabolic efficiency was estimated by calculating the psuedo-1st order rate constant from the metabolic constants by dividing Vmax/Km. In enterocyte microsomes, the CYP metabolic efficiency for metabolism to the oxon metabolites was approximately 28-fold greater for CPF than DZN. Compared on a per nmol P450 basis, the Vmax for CPF in enterocytes was approximately 2-3 times higher than in liver microsomes for the production of CPF-oxon and TCP. The Michaelis-Menten rate constant (Km) for the metabolism of CPF to CPF-oxon was comparable in liver and enterocyte microsomes; however, the enterocyte Km for TCP production was higher (indicating a lower affinity). The smaller volume of intestine, lower amount of CYP, and higher Km for TCP in the enterocyte microsomes, resulted in a lower catalytic efficiency (2 and 62 times) than in liver for oxon and TCP. PON1-mediated metabolism of CPF- and DZN-oxon was also demonstrated in liver and enterocyte microsomes. Although PON1 affinity for the substrates was comparable in hepatic and enterocytic microsomes, the Vmax were 48- to 275-fold higher, in the liver. These results suggest that intestinal metabolism may impact the metabolism of CPF and DZN, especially following low-dose oral exposures.
毒死蜱（CPF）和二嗪农（DZN）是硫代磷有机磷酸酯（OP）杀虫剂；它们的毒性分别通过细胞色素P450（CYP）代谢为毒死蜱-氧磷和二嗪农-氧磷来介导。相反，CYP也分别将这些OP解毒为三氯吡啶醇（TCP）和2-异丙基-4-甲基-6-羟基嘧啶（IMHP）。此外，A酯酶（PON1）对毒死蜱-氧磷和二嗪农-氧磷的代谢也形成TCP和IMHP。本研究评估了肠道和肝脏代谢在Sprague-Dawley大鼠中毒死蜱和二嗪农的活化和解毒过程中可能发挥的作用。在肝脏或分离的肠道肠细胞的微粒体中证实了类似的CYP和PON1介导的代谢谱。通过将Vmax/Km从代谢常数计算出伪一级速率常数来估计代谢效率。在肠细胞微粒体中，CYP将CPF代谢为氧磷代谢物的代谢效率比DZN高约28倍。以每纳摩尔P450为基础进行比较，肠细胞中CPF生成毒死蜱-氧磷和TCP的Vmax比肝脏微粒体中高约2-3倍。肝脏和肠细胞微粒体中CPF代谢为毒死蜱-氧磷的米氏速率常数（Km）相当；然而，肠细胞中TCP生成的Km较高（表明亲和力较低）。肠细胞微粒体中肠体积较小、CYP含量较低以及TCP的Km较高，导致其催化效率比肝脏中生成氧磷和TCP的效率低（分别低2倍和62倍）。肝脏和肠细胞微粒体中也证实了PON1介导的毒死蜱-氧磷和二嗪农-氧磷的代谢。尽管肝脏和肠细胞微粒体中PON1对底物的亲和力相当，但肝脏中的Vmax高48至275倍。这些结果表明，肠道代谢可能影响毒死蜱和二嗪农的代谢，尤其是在低剂量口服暴露后。
