Hematotoxicity inducing compound

The role of deacetylation in methemoglobinemia induced by acetanilide (4.101) and phenacetin (4.107) has been demonstrated. Indeed, concomitant i.p. administration of BNPP considerably reduced the hematotoxicity of these compounds [87]. Recent studies have shown that /V-hydroxyphenetidine (4.144), a metabolite of deacetylated phenacetin, is responsible for hemolysis and methemoglobin formation [88]. 

Hematotoxicity, defined as drug-induced altered production of peripheral blood cells, is most commonly associated with antiproliferative oncology compounds but is also caused by drugs for various indications, covering a wide pharmacology and chemical structure diversity (Table 17.1). This vast variety of chemical structures makes it difficult to predict hematotoxicity by in silica approaches and to model... 

Table 17.1 lists non-oncology compounds from diverse therapeutic, chemical, pharmacological areas and structures that induce clinical hematotoxicity. This demonstrates that bone marrow toxicity is not restricted to a small number of pharmacological or structural classes, thereby making it more difficult to understand specific mechanisms of toxicity. However, there are three classes of mechanisms of hematotoxicity, including antiproliferative, immune-mediated and other. Immune-mediated hematotoxicity and other indirect toxicities (e.g., a decrease of erythropoietin in kidney, leading to an impeded red cell production in the bone marrow) are not discussed in detail in this chapter as it requires involvement of the immune system or remote interactions and in vitro profiling assays have not been developed to detect these mechanisms. 

In many ways, mitochondria resemble bacteria for example, the mitochondrial ribosomal RNA genes of all eukaryotes have been traced back to the eubacteria [10]. This can explain why some antibacterial compounds with the target of inhibiting bacterial protein synthesis also inhibit mitochondrial protein synthesis [6, 11, 12], resulting in hematotoxicity. Tetracycline, chloramphemcol and some oxazolidinone antibiotics have been shown to induce hematotoxicity by inhibiting mitochondrial protein synthesis [13]. 

The AhR is expressed in bone marrow stromal cells [14] and human hematopoietic stem cells [15] and upon agonist binding the receptor translocates to the nucleus, resulting in altered transcriptional expression such as increased CYPlAl [16] and resulting in reactive oxygen species [17]. Nonpharmaceutical compounds such as TCDD, benzo(a)pyrene and benzene have been shown to induce hematotoxicity using this mechanism in vivo and in vitro [18, 19]. 

Although not a mechanism of hematotoxicity, polymorphic metabolism of a compound needs to be discussed since polymorphism can be associated with clinical hematotoxicity. For several compounds [28-39], one of the polymorphic enzymes increases exposure to the toxic form of the compound and thereby induces hematotoxicity in the patient, due to higher exposure levels and not due to a specific mechanism of toxicity within the patient populations. 

Tier 1 assay qualification entailed (i) evaluating compounds known to induce lineage specific hematotoxicity (ii) comparing the results from the myeloid tier 1 assay to the mouse CFU-GM assay (iii) comparing the results from the erythroid tier 1 assay to reduction in peripheral blood reticulocytes. 

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