Biotransformation and Enzymes Responsible for Metabolism of Pyrethroids in Mammals

摘要

Synthetic pyrethroids are used worldwide for controlling indoor and agricultural pests. Pyrethroids are metabolized by hydrolysis of ester bonds, oxidation at the acid and alcohol moieties and several conjugation reactions such as hydrophilic and lipophilic conjugates in laboratory animals and human beings. Along with progress of molecular biology, enzymes responsible for the metabolic reactions are elucidated mainly using genetically expressed enzymes. Ester hydrolysis was mediated by carboxylesterases(CESs) and oxidation by several cytochrome P450 (CYP) isoforms in rats and humans. Taking into account intrinsic clearance (CLint) and abundance, hCEl and hydrolase A are suggested to be a predominant CES in human and rat, respectively and CYP 2C9 and 3A4 in humans and CYP 2C6 and 2C11 (male) in rats to be major CYP isoforms. Enzymes involved in conjugation reactions of pyrethroids have not been well characterized with some exceptions. Pyrethroids are likely to be metabolized by combination of CESs or CYPs mainly in small intestine, liver or blood of rats and humans. Kinetic parameters derived from one pyrethroid may not represent those of all pyrethroids in rats or humans. For better extrapolation from rats to humans, CLint of intestine and liver with S9 (but not microsomes) and plasma (rats) should be compared in detail for each pyrethroid. In addition, it is desirable that interaction with transporters and plasma proteins is investigated for better understanding of absorption and distribution.