Single nucleotide polymorphism can alter liver enzyme interactions with drugs. PBMC samples provide genetic information predicting drug interaction outcome.
Blood sampling is easy and a relatively painless means of obtaining myriads of information about one’s physiology. In the serum component of blood we have numerous tests for antibodies, other proteins, and metabolites that can tell tales about several internal organs. Then there is the peripheral blood mononuclear cell or PBMC component which can be used to unravel other mysteries.
PBMC samples are useful for deciphering the makeup of a person at the molecular level. There are several commercially available kits that expedite DNA isolation from PBMC, although obtaining complete genome sequencing is laborious. Diagnostic kits bypass this hurdle through incorporating simple tests that manipulate DNA from PBMC to provide specific genetic information with relative ease.
Single nucleotide polymorphism or SNP is a DNA sequence variation in a gene which results in multiple forms of a single gene within the population. While the majority of SNP’s have no physiological consequence, a small fraction leads to diversity. This diversity includes differences in response to drugs.
Pharmaceuticals carried in blood pass through the liver where they interact with the cytochrome P450 family of isoenzymes. Some drugs are metabolized by these isoenzymes. Conversely, isoenzyme function can be affected by other drugs. Drug design can therefore become a 'cat and mouse' game where the drug maker is constantly trying to alter drug molecules in a manner that influences a favorable fate after a liver pass before the drug reaches its target organ.
In the cytochrome P450 family of isoenzymes, the CYP3A4 and CYP3A5 isoforms constitute 65% of all isoforms. Their importance lies in the fact that more than 6 out of 10 licensed drugs are known to interact with these isoenzymes. Introduce SNP into these isoenzymes and drug interaction suddenly becomes even more complex.
Using PBMC samples, a research group recently developed a new assay to catalog SNP’s in the CYP3A4 and CYP3A5 isoenzymes of the liver. Further, they collected PBMC samples from HIV-positive patients to determine if there were any correlations between drug resistance and these genes. While their dataset was small thereby limiting interpretation, the study demonstrated the utility of their assay.
At HemaCare we provide PBMC from several disease states including viral diseases such as HIV, HPV and HBV. We also provide PBMC from autoimmune disease states including celiac disease, crohn’s disease, rheumatoid arthritis, and lupus. Ease of access to disease state PBMC samples will no doubt contribute to the deciphering of genetic diversities that can enable or impede drug therapy intervention.
1: Berno G, et al. Analysis of single-nucleotide polymorphisms (SNPs) in human CYP3A4 and CYP3A5 genes: potential implications for the metabolism of HIV drugs. BMC Med Genet. 2014 Jul 2;15:76. doi: 10.1186/1471-2350-15-76. PMID: 24986243.