One promise of the Human Genome Project is that in the future, drug treatments will be tailored to individuals needs. Indeed, physicians will be able to take into consideration how well a patient can handle a drug based on his or her genes. Now researchers are beginning to make good on this promise: in todays Nature Genetics, they describe how different versions of a single gene can modulate responses to many medicines.
In particular, they looked at a kind of cytochrome P450 (CYP) enzyme. These enzymes break up a large number of chemicals, including drugs and toxins, and remove them from the body. Humans have about 55 different CYP genes belonging to various families. And members of the CYP3A family metabolize such important drugs as HIV protease inhibitors, calcium channel blockers, cholesterol-lowering drugs and cancer chemotherapeutics. The catch is that the amount of CYP3A proteins in the liver and small intestine can differ a great deal from one person to the next.
Scientists from the U.S., the U.K. and France have now found the reason: alleles of gene CYP3A5 that sometimes differ in just one DNA basea so-called single nucleotide polymorphism (SNP)lead to vastly different amounts of protein CYP3A5. This enzyme breaks down many drugs, but it also activates aflatoxin B1, a carcinogen. Depending on the allele, some people make no CYP3A5 at all; others, high amounts. African-Americans and Southeast Asians are more likely than Europeans, Japanese or Mexicans to possess an allele that produces a lot of CYP3A5.
Thus, the allele can probably predict how well a person will respond to a drug. "Simple DNA-based tests can now be used to determine how individual differences in CYP3A5 contribute to the overall metabolic fate of these CYP3A substrates," the authors conclude in their paper.