Deficient Enzyme Activity Leading to Rerouting of Metabolism

If a metabolic pathway that is responsible for the detoxification of a drug is deficient in an individual, the drug may be rerouted via another pathway that may lead to the formation of a toxic metabolite. This has been suggested for phenacetin, an analgesic that was withdrawn from the United Kingdom because of its potential to cause nephrotoxicity, carcinogenicity, and methaemoglobinemia (57-59). The first step in phenacetin metabolism is O-de-ethylation by cytochrome P450 1A2 (CYP1A2), which results in the formation of paracetamol. Further metabolism involves conjugation with glucuronide, sulfate, or glutathione that enables urinary excretion of the products. CYP1A2 metabolism has been implicated in toxicity of phenacetin (60,61). Numerous polymorphisms have been shown in the CYP1A2 gene, some of which are capable of altering the metabolic capacity of the enzyme (62-64). Low catalytic activity of CYP1A2*11 allelic variant leads to reduced phenacetin O-de-ethylation (64). Peters et al. (65) examined the role of CYP1A2 in the toxicity and carcinogenicity of phenacetin in CYP1A2 knockout mice. They found that metabolism of phenacetin by CYP1A2 reduces its toxicity in the liver, kidney, and spleen, indicating that metabolism with CYP1A2 may protect against toxicity. It is therefore possible that in the absence of CYP1A2, other metabolic pathways may be enhanced leading to increased toxicity and carcinogenicity of phenacetin (65-68).

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