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 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].
Footnotes
-
This work was supported by Grant-in-Aid 13027256 for Scientific Research on Priority Area from the Japanese Ministry of Education, Science, Sports, and Culture and Grant-in-Aid C13672343 for Scientific Research from the Japan Society for the Promotion of Science.
- Abbreviations used are::
- CYP
- cytochrome P450
- p,p′-DDE
- 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene
- p,p′-DDD
- 1,1-dichloro-2,2-bis(4-chlorophenyl)ethane
- p,p′-DDA
- 2,2-bis(4-chlorophenyl)acetic acid
- p,p′-DDMU
- 1-chloro-2,2-bis(4-chlorophenyl)ethylene
- HPLC
- high-performance liquid chromatography
- TLC
- thin-layer chromatography
- SKF 525-A
- proadifen hydrochloride
- Received July 9, 2001.
- Accepted October 18, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|