Gene Polymorphisms Complicate Metabolic Studies

When it comes to testing the pharmacokinetics of drugs, pesticides or other xenobiotics (man-made compounds), we often turn to other animal species such as rats and mice. However, when interpreting the data we collect, it’s very important to remember that, while there are many similarities in terms of the metabolic pathways in mammalian cells, there are also many differences in the enzymes that execute those pathways. The cytochrome P450 enzyme group is the predominant class of enzymes in the liver for dealing with foreign chemicals. Not only are there species differences at the genetic level of these enzymes (polymorphisms) that result in slight differences in their activities and specificities for certain compounds, there are also differences at the level of transcription (caused by polymorphisms in transcriptional machinery), dictating how much of each enzyme we may produce in our bodies.

One enzyme responsible for much of the conversion of pro-carcinogens to their carcinogenic form in our bodies, P450 1A2, is known to be 75% identical between rats and humans. However, depending on the substrate, N-hydroxylation activities can vary by an order of magnitude between the species. Add to that the fact that there are considerable differences among species themselves such as humans of different family lineages or races, and genders. N-hydroxylation by P450 1A2 has been found to vary by as much as 40% between human individuals. Gene polymorphisms, or these differences between individuals, is the basis of RFLP analysis (think DNA fingerprinting). This is why interpreting the data from drug, or other metabolism studies, is much more complex than it may appear on the surface.

_Sources:

Uno S. et al. 2009. CYP1A1 and CYP1A2 expression: comparing ‘humanized’ mouse line and wild-type mice: comparing human and mouse hepatoma-derived cell lines. Toxicol. appl Pharmacol. 237(1):119-26.

Kirchheiner et al. 2005. Effect of genetic polymorphisms in cytochrome P450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin Pharmacokinet. 44(12):1209-25.

Kuribayashi et al. 2009. Human cytochrome P450 1A2 involvement in the formation of reactive metaoblites from a species-specific hepatotoxic pyrazolopyrimidine derivative, 5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimidine. Chem Res Toxicol. 22(2):323-31.

Guengerich FP. et al. 1999. Inter-individual differences in the metabolism of environmental toxicants: cytochrome P450 1A2 as a prototype. Mutat Res. 428(1-2):115-24.

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