The induction of cytochrome P-450 by isosafrole and related methylenedioxyphenyl compounds.
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.
D000818:Animals; D003433:Crosses, Genetic; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003600:Cytosol / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology*; D004790:Enzyme Induction; D006838:Hydrocarbons / Q000378:metabolism*; D007536:Isomerism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000302:isolation & purification / Q000378:metabolism*; D012451:Safrole / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013045:Species Specificity; D013329:Structure-Activity Relationship
D004149:Dioxoles; D006838:Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D012451:Safrole; C015959:isosafrole