Hello All,

I very commonly read papers in my field dealing with pesticide detoxification and metabolism in insects. Most commonly the different types of proteins responsible for xenobiotic metabolism such as cytochrome P450s, glutathione-S transferases and ABC transporters are categorized into “phases” into three phases (I, II, and III respectively).

The story goes that phase I metabolizers (e.g. P450s) modify xenobiotics in a way that makes them suitable substrates for conjugation via phase II enzymes (e.g. GSTs). After phase II metabolism, the compound becomes a suitable substrate for phase III transporter proteins (e.g. ABCs) and is removed from the cell and then body.

However, there don’t appear to be many examples of this in the literature. The original nomenclature appears to come from a single chapter in a book, which I haven’t been able to track down the text for (Williams 1959). While there are some examples for linking phase I and phase II reactions, a review I found suggested that these cases are note representative (David Josephy et al. 2005)⁠. This review was also very critical of the entire concept of phase I and II and suggested it is an artifact which has been repeated with limited evidence. Likewise, although there are examples of phase II and phase III interactions (Morrow et al. 1998)⁠ many ABC transporters have been shown to act on unmodified compounds.

With this being said, my three questions for this discussion would be

1) What is the evidence for sequential metabolism in the phase I, II, III in insects?

2) How widespread is this phenomenon in any organism?

3) Should this terminology be used when discussing xenobiotic metabolism?

Bibliography

David Josephy P, Peter Guengerich F, Miners JO. 2005. “Phase I and Phase II” Drug Metabolism: Terminology that we Should Phase Out? Drug Metab. Rev. [Internet] 37:575–580. Available from: http://www.tandfonline.com/doi/full/10.1080/03602530500251220

Morrow CS, Smitherman PK, Diah SK, Schneider E, Townsend AJ. 1998. Coordinated action of glutathione S-transferases (GSTs) and multidrug resistance protein 1 (MRP1) in antineoplastic drug detoxification. Mechanism of GST A1-1- and MRP1-associated resistance to chlorambucil in MCF7 breast carcinoma cells. J. Biol. Chem. [Internet] 273:20114–20120. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9685354

Williams, R. T. (1959). Detoxication Mechanisms: The Metabolism and Detoxication of Drugs,Toxic Substances, and Other Organic Compounds. 2nd ed. London: Chapman and Hall