Structure-activity relationships on the induction of hepatic microsomal enzymes in the mouse by 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane(DDT) analogs.
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Biomedical subjects
Publications and source records attributed to E Hodgson.
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5 cytochrome P-450 isozymes were purified from the livers of uninduced mice and reconstituted with purified NADPH cytochrome P-450 reductase and phospholipid. The pesticides parathion, fonofos, DEF, Mocap and profenofos were oxidized by the reconstituted monooxygenase system to form acetylcholinesterase (AChE) inhibitors. The bioactivation varied with the pesticide substrate and the cytochrome P-450 isozyme. Aldrin epoxidation occurred with all 5 isozymes, with cytochrome P-450 A1 being the most active. All fraction metabolized the pesticide synergist piperonyl butoxide (PBO) to form an inhibitory cytochrome P-450-PBO-metabolite complex. The reduced complex produced a spectrum in the Soret region which was characteristic for each of the cytochrome P-450 isozymes. Inhibition of aldrin epoxidation by PBO was found to be unrelated to the nature of the Soret spectrum.
Using sucrose gradients, the Ah receptor and a 3-4S binding peak were measured in hepatic cytosol from Dub: ICR, C57BL/6, and DBA/2 male mice. Isosafrole, piperonyl butoxide, and 5-t-butyl-1,3-benzodioxole were unable to displace 2,3,7,8-tetrachlorodibenzo-p-dioxin or 3-methylcholanthrene from either the Ah receptor or the 3-4S binding peak, in vitro. In in vivo experiments, treatment of C57BL/6 mice with 3-methylcholanthrene caused a 4-fold reduction in Ah receptor binding 2 h after i.p. injection; whereas, isosafrole caused a 2-fold enhancement of the Ah receptor after 24 h. This increase in the Ah receptor binding following isosafrole treatment may be due to induction. 3-Methylcholanthrene treatment of C57BL/6 mice also caused a 3-fold reduction in the 3-4S binding peak 2 h after i.p. injection; isosafrole treatment had little or no effect on the 3-4S peak in C57BL/6 or DBA/2 mice. Both in vivo and in vitro data appear to demonstrate that there is no direct role for the Ah receptor or the 3-4S protein in the regulation of cytochrome P-450 by methylenedioxyphenyl compounds. Using Sephadex G-100 chromatography, a cytosolic protein fraction was obtained from C57BL/6 and Dub:ICR mice which was previously implicated by others as a carrier in the metabolism of benzo[a]pyrene (B[a]P). This fraction was applied to sucrose gradients and sedimented in the 3-4S region. Hence it appears that the 3-4S binding peak may be the carrier described by these workers.
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