Heme sequestration

The mechanism of the acute kidney injury is thought to be multifactorial and similar to other cases of myoglobinuric renal failure [118, 121-126]. These factors include obstruction of tubules, toxic effects of the pigment or iron on renal tubular cells and altered hemodynamics in association with inhibition of the vasodilator nitric oxide by myoglobin. Experimental animals exposed to heme pigment have increases in the renal synthesis of both heme oxidase and ferritin [125]. This allows for more rapid heme degradation and greater sequestration of potentially toxic iron by the tubular cells [125]. Whether narcotics or the hypotensive, hypoxic environment associated with rhabdomyolysis interfere with these protective effects of the kidney is unknown. 

In any case, it is clear that artemisininoids act by an alkylant mechanism and that this mechanism differs from that shown by other alkylant STLs as discussed above. It is highly noteworthy that selective toxicity occurs towards various states in the life-cycle of Plasmodium since heme-associated toxification by the described mechanism should occur also in uninfected cells. This selectivity is likely to be -at least in part- due to selective sequestration in infected erythrocytes as mentioned above. Evidence has been presented that -apart from targeting malaria-specific proteins- processes consuming metabolic energy, i.e. active transport, is involved in this selective uptake [92] but the transport mechanism is not known in detail. 

Many different mechanisms to mediate heavy metal resistance in prokaryotes exist, and have been carefully reviewed elsewhere (Ralston and O Halloran 1990 O Halloran 1993). In eukaryotes, this job is done by metallothioneins which sequester heavy metal ions and make them unavailable to exert toxic effects (reviewed by Hamer 1986 Andrews 1990). In this regard, heme-hepoxin induces both heme oxygenase and MT expression in human promyelocytic leukaemia cells and mouse hepatoma cells (Alam et al. 1989). The authors suggest that MT may sequester the nontoxic metal zinc, which would otherwise compete with Fe for occupation of sites on Fe-dependent regulatory proteins such as the IRE-BP. Thus, it is possible that sequestration of metals by MT could mediate, not only the direct toxic effect of such metals (reviewed in Chap. 1, this volume), but... 

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