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Xenobiotica
the fate of foreign compounds in biological systems
Volume 51, 2021 - Issue 10
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Molecular Toxicology

Intracellular activation of 4-hydroxycyclophosphamide into a DNA-alkylating agent in human leucocytes

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 1188-1198 | Received 06 Jul 2021, Accepted 27 Aug 2021, Published online: 08 Sep 2021
 

Abstract

1.The conversion of the cyclophosphamide intermediate metabolite 4-hydroxycyclophosphamide (4-OHCP) to the final cytotoxic metabolite phosphoramide mustard (PAM) is classically assumed to occur via chemical hydrolysis of the phospho-ester bond. Whilst it has been suggested previously that this reaction could be enzyme-catalysed, there was only indirect evidence for this (i.e. formation of the by-product acrolein).

2. Using an assay to detect formation of DNA-alkylating adducts which block PCR amplification (QPCR-block assay), we have demonstrated that 4-OHCP can be activated by peripheral blood mononuclear cells (PBMC). The DNA-alkylating potency of 4-OHCP in PBMC increased >18-fold compared to the intrinsic reactivity of 4-OHCP for purified gDNA.

3. We also found that immortalised T-cells (Jurkat) had a similar ability to activate 4-OHCP into a DNA alkylating agent, whereas there was no appreciable activation in epithelial derived (Caco-2) cells. This suggests the possibility of tissue-specific enzyme expression.

4. Of the candidate enzymes tested only recombinant human cAMP-phosphodiesterase-PDE4B and snake-venom phosphodiesterase (PDE-I) could catalyse this activation into a DNA-alkylating agent.

5. This enzymatic catalysis of the phospho-ester bond (P-O-C) is a hitherto unrecognised feature of this important immunomodulatory drug and should be investigated further.

Disclosure statement

No potential conflict of interest was reported by the author(s).

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