Mechanisms for selective toxicity of fipronil insecticide and its sulfone metabolite and desulfinyl photoproduct
Mechanisms for selective toxicity of fipronil insecticide and its sulfone metabolite and desulfinyl photoproduct
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DOI：
10.1021/tx980157t
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发表时间：
1998-12-01
影响因子：
4.1
通讯作者：
Casida, JE
中科院分区：
文献类型：
--
作者：
Hainzl, D;Cole, LM;Casida, JE
氟虫腈是一种具有三氟甲基亚磺酰基取代基的N-苯基吡唑，是第二代杀虫剂，作用于γ-氨基丁酸（GABA）受体，阻断氯离子通道。第一代包括多氯环烷烃、甲型硫丹和林丹。在这项研究中，我们研究了亚砜氟虫腈及其砜代谢产物和双氯芬酰光产物相对于其靶位点相互作用的体外和离体选择性毒性机制，以及生物氧化对砜的氟虫腈作用的重要性。通过从非竞争性阻滞剂位点置换4 '-乙炔基-4-n-[2，3-H-3（2）]-丙基双环原苯甲酸酯（[H-3]EBOB），测定GABA受体敏感性的差异，似乎是氟虫腈对昆虫（家蝇和果蝇！在昆虫中，非泼罗尼及其砜和双烯酰衍生物的IC（50）范围为3至12 nM，而在脊椎动物中，非泼罗尼、非泼罗尼砜和双烯酰非泼罗尼的IC（50）平均值分别为1103、175和129 nM。分别相对于脊椎动物，昆虫的特异性依次降低：氟虫腈>林虫腈>氟虫腈砜> α-硫丹。在LD 50剂量下，非泼罗尼及其砜和双烯丙基磺酰衍生物对小鼠脑中[H-3]EBOB结合的离体抑制作用相似，但令人惊讶的是，在较高剂量下，非泼罗尼可能是致死性的，而不会可检测地阻断[H-3]EBOB位点。P450抑制剂胡椒基丁醚在家蝇中起作用，增加了非泼罗尼和砜的代谢稳定性和有效性，但对二甲双胍化合物没有影响，在小鼠中，它完全阻断亚砜向砜的转化，而不改变中毒。因此，氟虫腈和氟虫腈衍生残留物的选择性毒性部分是由于母体化合物对昆虫的效力高于哺乳动物GABA受体，但也取决于转化为更具持久性和选择性较低的砜代谢物和双氯芬酰光产物的相对速率。
Fipronil, an N-phenylpyrazole with a trifluoromethylsulfinyl substituent, initiated the second generation of insecticides acting at the gamma-aminobutyric acid (GABA) receptor to block the chloride channel. The first generation includes the polychlorocycloalkanes alpha-endosulfan and Lindane. In this study, we examine the mechanisms for selective toxicity of the sulfoxide fipronil and its sulfone metabolite and desulfinyl photoproduct relative to their target site interactions in vitro and ex vivo and the importance in fipronil action of biooxidation to the sulfone. Differences in GABA receptor sensitivity, assayed by displacement of 4'-ethynyl-4-n-[2,3-H-3(2)]-propylbicycloorthobenzoate ([H-3]EBOB) from the noncompetitive blocker site, appear to be a major factor in fipronil being much more toxic to the insects (housefly and fruit fly! than to the vertebrates (humans, dogs, mice, chickens, quail, and salmon) examined; in insects, the IC(50)s range from 3 to 12 nM for fipronil and its sulfone and desulfinyl derivatives, while in vertebrates, the IC50 average values are 1103, 175, and 129 nM for fipronil, fipronil sulfone, and desulfinyl fipronil? respectively. The insect relative to the vertebrate specificity decreases in the following order: fipronil > lindane > desulfinyl fipronil > fipronil sulfone > alpha-endosulfan. Ex vivo inhibition of [H-3]EBOB binding in mouse brain is similar for fipronil and its sulfone and desulfinyl derivatives at the LD50 dose, but surprisingly, at higher doses fipronil can be lethal without detectably blocking the [H-3]EBOB site. The P450 inhibitor piperonyl butoxide, acting in houseflies, increases the metabolic stability and effectiveness of fipronil and the sulfone but not those of the desulfinyl compound, and in mice it completely blocks the sulfoxide to sulfone conversion without altering the poisoning. Thus, the selective toxicity of fipronil and fipronil-derived residues is due in part to the higher potency of the parent compound at the insect versus the mammalian GABA receptor but is also dependent on the relative rates of conversion to the more persistent and less selective sulfone metabolite and desulfinyl photoproduct.