Metabolic Activation of Toxicity

ACTIVTox is sensitive to metabolically activated toxins

Some compounds are not direct toxins but require metabolic activation to exhibit their toxicity (1). Aflatoxin B1, a classic liver toxin, is such a compound. It is converted by CYP3A to a highly reactive epoxide, the actual toxic metabolite. ACTIVTox cells were incubated with the indicated concentration of aflatoxin B1 for 48 hours in the presence or absence of 10µM ketoconazole. Figure 1 shows that aflatoxin B1 kills the ACTIVTox cells at concentrations seen in primary hepatocytes and that this toxicity is reduced by blocking CYP3A metabolism with ketoconazole. ACTIVTox identifies compounds that require metabolic activation.

Figure 1. Aflatoxin is metabolized to the toxic epoxide by CYP3A

The opposite is also true, where a metabolite is less toxic than the parent compound. Terfenadine and its CYP3A metabolite, fexofenadine, provide such an example. Terfenadine, marketed as Seldane, was a leading antihistamine until liver toxicity was discovered among users. Terfenadine is metabolized by CYP3A to fexofenadine, shown below. In another of the ACTIVTox assays, inhibition of proliferation, terfenadine is very toxic, inhibiting cell growth at concentrations as low as a few micromolar. Fexofenadine, by comparison, shows no effect in this assay, even at millimolar concentrations.

Figure 2. Terfenadine is toxic while its metabolite, fexofenadine, is not.

A final requirement for any predictive toxicity system is that it correctly identify compounds that are toxic in humans. Animal systems often over predict or under predict toxicity in humans. Tamoxifen is a compound that exhibits liver toxicity in rats but not in humans. Rats form only the sulfate metabolite of tamoxifen while humans form both the sulfate and the glucuronide. ACTIVTox correctly predicts that tamoxifen is not an hepatotoxin in humans.

References

  1. Park, B.K., et al. (2005) The role of metabolic activation in drug-induced hepatotoxicity. Annu. Rev. Pharmacol. Toxicol. 45, 177 – 202.

Data Sets

We have screened thousands of compounds in the ACTIVTox assays.

Download data sets featuring a variety of these compounds assayed with the ACTIVTox kits.

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