Interactions with glutathione S-transferases of porphyrins used in photodynamic therapy and naturally occurring porphyrins

Abstract

Several naturally occurring porphyrins and porphyrins used in photodynamic therapy inhibit glutathione S-transferase isoenzymes either purified from rat liver or lung or in cytosol from normal and from cancerous (Morris 7288C hepatoma) liver. Although differences occur in the type and amount of transferases in normal and cancerous liver and in the liver of rats bearing an extrahepatic tumour, these enzymes are potential binding sites for porphyrins. Porphyrin structure is an important factor in determining the affinity of binding, as shown by the relative inhibitory effectiveness. Of the dicarboxylic porphyrins in the mixture used clinically, OO'-diacetylhaematoporphyrin and monohydroxyethylmonovinyldeuteroporphyrin are more effective inhibitors than haematoporphyrin and protoporphyrin IX. Of the naturally occurring porphyrins the order of effectiveness is protoporphyrin IX (dicarboxylic) greater than coproporphyrin (tetracarboxylic) greater than uroporphyrin (octacarboxylic) and type I greater than type III isomers of both uroporphyrin and coproporphyrin, and the synthetic tetra-meso-phenylporphinetetrasulphonate is a better inhibitor (apparent Ki = 250 nM) than coproporphyrin, which contains a comparable number of negative charges. In addition, iron-porphyrin chelates are more effective inhibitors of the transferases, with 25-fold decrease in Ki value, than the free porphyrins. These results indicate that one means whereby porphyrins accumulate in tissues is the occupation of intracellular binding sites, such as the transferases. Since porphyrins inhibit the activity of these important detoxifying enzymes, there will be metabolic consequences to the cell.

A Novel Antioxidant Role for Ligandin Behavior of Glutathione S-Transferases: Attenuation of the Photodynamic Effects of Hypericin

“…Regardless of the uncertainty of the inhibition mechanism, these results demonstrate high-affinity interactions between HYP and A1-1 and P1-1. Notably, HYP is a significantly more potent inhibitor than the prototypical ligand inhibitors, such as hematoporphyrin IX, that have K I values in the range 1-50 µM (28,43,44). Similarly, HYP is a much more potent inhibitor of these GSTs than other proteins, for which HYPdependent inhibition has been observed.…”

“…Interestingly, GSTs also possess a noncatalytic ligand-binding function, wherein they sequester hydrophobic planar aromatic ligands, such as dianthraquinones, at a poorly defined binding site or sites. Binding of steroids, hemes, and other ligands at this GST site(s) may alter their tissue distribution ( , ). This GST site has been referred to as the “ligandin” site.…”

The chemistry and biology of inhibitors and pro-drugs targeted to glutathione S-transferases

“…62,2005 Review Article 1227 Figure 7. Bivalent inhibitors based on the GS-CDNB conjugate (14) and on the ligandin-type inhibitor cibacron blue (15).…”

“…The structural, functional and evolutionary relationships between these GST classes are summarized elsewhere [12]. In addition to the well-established GSH conjugation activity, several cytosolic GSTs have also been suggested to modulate cellular uptake and distribution of planar aromatic compounds, usually with anionic functional groups [14][15][16]. This 'ligandin' behavior was first appreciated for the GSTA1-1 and related rat isoform, although other isoforms appear to have a similar ability to bind non-substrate ligands with analogous structures at a site that is not well defined by available structural models.…”

Factors responsible for the formation of different N-alkylated porphyrins in rat liver microsomal systems exposed to norethindrone. The role of 3 α-hydroxysteroid dehydrogenase

“…3b). Purification and identity of GP converting activity Liver cytosolic glutathione transferases bind steroids and porphyrins (Smith et al, 1985). It was originally considered that the GP converting protein might be the same as this enzyme.…”