Structural requirements for substrates of cytochromes P-450 and P-448

Up-regulation of the CYP1 family in rat and human liver by the aliphatic isothiocyanates erucin and sulforaphane

“…Extensive studies have shown that the inducers of the CYP1 family are essentially aromatic planar compounds, characterised by a large area/depth 2 ratio (Lewis et al, 1986;1987). The most avid ligand to this receptor is the toxin TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), and strong agonists are mostly large hydrophobic planar aromatic compounds such as the polycyclic aromatic hydrocarbons (Cheung et al 1993;Machala et al, 2001;Denison and Nagy, 2003;Pushparajah et al, 2007), although compounds comprising a single substituted aromatic ring, such as diaminotoluenes, can also serve as agonists (Cheung et al, 1996).…”

Multifunctional receptor model for dioxin and related compound toxic action: possible thyroid hormone-responsive effector-linked site.

“…Other workers (39) have also stressed the importance of aromatic-aromatic interactions in the binding sites of cytochromes P-448 (to which the Ah receptor is related). Although experimentally, hydroxyCAHs have relatively much lower binding affinities than their halogen substituted counterparts, the model would predict that this is due to large differences in aqueous desolvation energy (because of the potential for hydrogen bonding) rather than to differences in intrinsic binding properties (29).…”

Structure Antimutagenicity Relationship of Anthraquinones

“…Taken the above considerations together one may conclude that all quinones which meet the criteria established by Lewis et al [65] may be effective inhibitors of polycyclic and heteroaromatic mutagens in S. typhimurium. Inhibition of P-450-dependent mono-oxygenases by quinones was demonstrated in several studies with subcellular liver fractions in vitro.…”

“…In a theoretical study by Lewis et al [65], based on molecular orbital calculations and molecular graphics, structural requirements for hydroxylation of xenobiotica by cytochrome P-450-dependent mono-oxygenases were outlined. Substrates with fused aromatic or heteroaromatic rings such as benzo[α]pyrene (BaP) and IQ gave rise to overall molecular planarity with relatively small molecular depth.…”

“…Among these AQs; aloe-emodin, chrysophanol, emodin and physicon were active against Trp-P-1, Trp-P-2 and other HAAs [50], various anthraquinone derivatives were active against the ultimate mutagenic metabolite of BaP. The 7,8-diol-9,10-epoxide of anthraflavic acid showed activity against IQ [65], while emodin was active against IQ, Trp-P-2, and BaP of tanshinones. Tetracyclic heterocyclic quinones isolated from the radix of Salvia miltiorrhiza revealed activity against Trp-P-1 and BaP [51].…”