Reductive Metabolism ofp,p′-DDT ando,p′-DDT by Rat Liver Cytochrome P450

Abstract

This paper is available online at http://dmd.aspetjournals.org ABSTRACT:The in vitro metabolism of p,p-DDT [1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane], an important environmental pollutant, was examined in rat liver, focusing on reductive dechlorination. When p,p-DDT was incubated with liver microsomes of rats in the presence of NADPH or NADH, a dechlorinated metabolite, p,p-DDD [1,1-dichloro-2,2-bis(4-chlorophenyl)ethane], was formed under anaerobic conditions together with a dehydrochlorinated metabolite, p,p-DDE [1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene]. p,p-DDE was also formed from p,p-DDD by liver microsomes. The dechlorinating activity was inhibited by carbon monoxide, metyrapone, and SKF 525-A (proadifen hydrochloride), but the dehydrochlorinating activity was unaffected. The reductase activity toward p,p-DDT was induced by the pretreatment of rats with phenobarbital and dexamethasone. The dechlorination was catalyzed enzymatically by recombinant cytochrome P450 2B1, 3A1, 2B6, and 3A4. When p,p-DDT was incubated with liver microsomes of rats in the presence of both a reduced pyridine nucleotide and FMN, p,p-DDD was also formed under anaerobic conditions. In this case, the dechlorinating activity was not abolished when the microsomes were boiled. The reductase activities were inhibited by carbon monoxide. Hematin exhibited reductase activity toward p,p-DDT in the presence of NADH and FMN. The activity of hematin was also supported by FMNH 2 . The reductive dechlorination also seems to proceed nonenzymatically with the reduced flavin, catalyzed by the heme group of cytochrome P450. Similar enzymatic and nonenzymatic reducing activities were observed toward o,p-DDT [1,1,1-trichloro-2,2-bis(2-chlorophenyl-4-chlorophenyl)ethane].

Comparative molecular modeling of Anopheles gambiae CYP6Z1, a mosquito P450 capable of metabolizing DDT

“…The docked conformations were sorted in ascending order with respect to the total energy (the sum of van der Waals as well as electrostatic energy terms of the potential energy function and the ligand's internal energy). The binding modes with the lowest total energies and known hydroxylation sites [trichloromethyl group in DDT (20,37); carbons 4-7 in carbaryl (38); furan ring in xanthotoxin (39)] closest to the heme were chosen for the second round of energy minimization during which all side chains were allowed to move freely.…”

A P450 gene associated with robust resistance to DDT in ciliated protozoan, Tetrahymena thermophila by efficient degradation

“…5(a)), indicating CYP5013C2 participates in the metabolism of DDT in Tetrahymena. P450 of rat liver is involved in the reductive dechlorination of DDT to DDD, but not to DDE (Kitamura et al, 2002). Our results showed that there were no significant differences in concentrations of DDE among strains of p450-KD, WT, and p450-OE (Fig.…”

“…Previous studies established that, in rat, most production of DDD is catalyzed enzymatically by the cytochrome P450 through reductive dechlorination of DDT (Kitamura et al, 2002). We therefore sought to test whether this Tetrahymena P450 functioned similarly in the metabolism of DDT.…”

“…In rats, cytochrome P450 monooxygenases (P450s) play important roles in the reductive dechlorination of DDT to DDD (Kitamura et al, 2002). In Anopheles gambiae, DDT is also metabolized by P450, which enables mosquitoes to acquire resistance (Chiu et al, 2008).…”

Organochlorine Pesticides in the Coastal Sediment of Citarum Estuary, Jakarta Bay: The Imp Ortant Role of Fine Fraction of the Sediment as Their Agent Transport and Processes of Their Early Diagenesis

“…Walaupun termasuk senyawa persisten, DDT di lingkungan dihadapkan berbagai proses yang menyebabkan perubahan-perubahan strukturnya dan membentuk DDD dan DDE, serta pada tingkatan tertentu membentuk DDMU dan DDA (Quensen III et al, 1998;Kitamura et al, 2002). Kondisi lingkungan redoks diakui sebagai faktor penentu perubahan-perubahan DDT menjadi metabolitnya.…”