Suramin: an inhibitor of the final steps of the mineralocorticoid pathway?
The authors used incubated adrenal mitochondria to study the in vitro effect of suramin, an antiparasitic drug, on the transformation of corticosterone and 18-hydroxycorticosterone into aldosterone. The results show that, under conditions preserving membrane integrity, the "impermeance" of suramin meant that concentrations similar to the plasma-levels reached in treated patients induced only slight inhibition of the final intramitochondrial steps in aldosterone synthesis. However, suramin strongly inhibited mitochondrial respiration. The inhibition of two intramitochondrial mechanisms (respiration and steroid synthesis) suggests that the effect of suramin involves partial inhibition of metabolic intermediate carriers. The inhibition of the activity of various extramitochondrial enzymes involved in intermediate metabolism, suggests that the inhibition of steroid biosynthesis can be explained only on the basis of an extramitochondrial action of suramin. The action of suramin must, therefore, primarily and directly affect extramitochondrial steroid synthesis and only indirectly affect intramitochondrial steroid synthesis as a result of an impact on the reducing equivalent supply. However, even if suramin does not bind to cytochrome P450 11 beta which catalyzes the final steps of aldosterone biosynthesis pathway, this does not imply that suramin has no direct effect on steroid synthesis within the mitochondria, in addition to its toxic effects, particularly if the cell structure is disrupted (as is often the case in tumor tissues).
Zenatti
M
M
Service de Biochimie Médicale, Faculté de Médecine Pitié-Salpétrière, Paris, France.
Blanchouin-Emeric
N
N
Koplewicz
S
S
Defaye
G
G
Aupetit-Faisant
B
B
D015069:18-Hydroxycorticosterone / Q000378:metabolism; D000311:Adrenal Glands / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D000450:Aldosterone / Q000096:biosynthesis; D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D004372:Ducks; D008293:Malates / Q000494:pharmacology; D008297:Male; D008901:Mineralocorticoids / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D013252:Steroid 11-beta-Hydroxylase / Q000378:metabolism; D013386:Succinates / Q000494:pharmacology; D019802:Succinic Acid; D013498:Suramin / Q000378:metabolism / Q000494:pharmacology*
D008293:Malates; D008901:Mineralocorticoids; D013386:Succinates; D000450:Aldosterone; D015069:18-Hydroxycorticosterone; D013498:Suramin; C030298:malic acid; D019802:Succinic Acid; D013252:Steroid 11-beta-Hydroxylase; D003345:Corticosterone