A Major Genetic Determinant Of Drug Clearance In Humans

People are not born equal when it comes to susceptibility to disease and response to treatment. The anesthetic drug midozolam, for example, lingers longer in the blood streams of some people than those of others. The reason for this is thought to lie, at least in part, in the genetic variation between people. For any given stretch of a human chromosome, it is estimated that two individuals will show variation at about 1 in every 1,000 bases of DNA sequence. One of the great challenges now faced by geneticists is to identify how the variable bases (called 'single nucleotide polymorphisms' (SNPs)) influence traits, such as drug response. The way in which genotype (defined, for example, by a particular SNP or combination of SNPs) governs and correlates with drug response has been dubbed 'pharmacogenetics', and received a great deal of fanfare, albeit with scant support from the research laboratory.

A group led by Erin Schuetz (of St Jude Children's Research Hospital, Memphis, Tennessee) has now found a major genetic determinant of drug clearance in humans (Nature Genetics, Vol. 27, Issue 4, 01 April 2001). They characterized the genes encoding the cytochrome P450 (CYP) proteins, which chemically modify and thus inactivate many toxic molecules-whether produced by the body itself or supplied by the environment. They focused on the CYP3A family, members of which account for the inactivation of 50% of all drugs--including HIV protease inhibitors, immunosuppressants, and anti-cancer and cholesterol-lowering chemicals. Using the DNA of people in different groups, they identified the most common SNPs in the CYP3A genes and then looked for possible associations between these SNPs and differences in drug detoxification.

Among several significant associations, they found one SNP (CYP3A5*3) that results in a shorter, and presumably less active, CYP3A5 protein. By measuring the rate at which different individuals break down midazolam, Schuetz and colleagues were able to draw a correlation between type of SNP (or genotype) and ability to metabolize the drug. Consistent with prediction, people with the CP3A5*3 allele break down the drug midazolam more slowly than those carrying the CYP3A5*1 allele, which encodes a full-length protein. They are therefore more likely to respond more efficiently to standard doses of many therapeutic agents. They may also have a higher risk of developing diseases promoted by other CYP3A target molecules-such as the hormone estrogen, which can promote breast cancer.

As the full-length CYP3A5*1 allele typically accounts for over 50% of total CYP3A activity when intact, it may be that the CYP3A5 alleles contribute substantially to the clearance of drugs and other relevant targets. The study by Schuetz and colleagues opens the door to a more accurate assessment of risk of disease and improvements in tailoring the prescription of drugs.

CONTACT:

Dr. Erin Schuetz
St. Jude Children's Research Hospital
Memphis, Tennessee, USA
Telephone: +1 (901) 495 2205
Fax: +1 (901) 525 6869
e-mail: erin.schuetz@stjude.org

Dr. Mark Boguski
Rosetta Inpharmatics
Kirkland, Washington, USA
Telephone: +1 (425) 820 8900
Fax: +1 (425) 820 5757
e-mail: mboguski@rii.com

(C) Nature Genetics press release.

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