RT Journal Article
SR Electronic
T1 Reductive Metabolism of<em>p</em>,<em>p</em>′-DDT and<em>o</em>,<em>p</em>′-DDT by Rat Liver Cytochrome P450
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 113
OP 118
DO 10.1124/dmd.30.2.113
VO 30
IS 2
A1 Shigeyuki Kitamura
A1 Yuri Shimizu
A1 Yuko Shiraga
A1 Mayumi Yoshida
A1 Kazumi Sugihara
A1 Shigeru Ohta
YR 2002
UL http://dmd.aspetjournals.org/content/30/2/113.abstract
AB 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 fromp,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. Whenp,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 towardp,p′-DDT in the presence of NADH and FMN. The activity of hematin was also supported by FMNH2. 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]. The American Society for Pharmacology and Experimental Therapeutics