KAUAI, HAWAII – When it comes to the body’s ability to metabolize medications, ancestry matters.
"In our clinical experience we know that some patients respond [to certain medications] and others don’t," Dr. Keh-Ming Lin said at the annual meeting of the American College of Psychiatrists. "There are also toxic responders, even though we give them the same type of treatment. Right now, we don’t have a way of identifying who will respond or who will have serious side effects.
Dr. Keh-Ming Lin
"This occurs although humans are 99.99% the same from a genetic standpoint," said Dr. Lin, a psychiatrist at the University of California, Los Angeles. "We have the same chromosome structures and the same number of genes, and the genes are structured in the same way. It often just takes one single mutation to alter the function of the genes. As a result, there are individual and ethnic differences in the way genes respond to treatment."
Variations in pharmacokinetics are mediated by a number of cytochrome P450 enzymes (CYPs), he said, including CYP2D6, CYP3A4, and CYP1A2. "These enzyme activities are determined not only by genetic dispositions but also by environmental factors like diet and herbs that people take," said Dr. Lin, who is also a distinguished life fellow of the American Psychiatric Association.
He described CYP2D6 as "interesting" for at least two reasons: First, it is involved in about 40% of all drugs currently on the market, including many antidepressants, neuroleptics, drugs of abuse, cardiovascular drugs, and antiemetics. Second, there are different mutations of CYP2D6 that translate to four different rates of metabolism. For example, genotype CYP2D6*4 is associated with very slow rates of metabolism (PM); genotypes CYP2D6*17 and CYP2D6*10 are associated with slow rates of metabolism (SM); CYP2D6 is associated with normal rates of metabolism (EM), and genotypes CYP2D6*1XN and CYP2D6*2XN are associated with fast rates of metabolism (UM).
"These could be determined by a simple genetic test," Dr. Lin said. "We have known for about 40 years that Asians seem to be more sensitive to medication and need a lower dosage of some of the commonly prescribed drugs. Part of this may be because a higher proportion of East Asians are slow metabolizers due to a specific gene mutation. On the other hand, about 9% of Caucasians are poor metabolizers. They have absolutely no CYP2D6, so they tend to be very sensitive to medication."
Dr. Lin also noted that a high proportion of people who are part of certain ethnic groups metabolize drugs very rapidly, including Ethiopians, Arabs, Melanesians, and others of East African descent. "They require much larger doses of medication to have the same effect," he said.
Such differences occur because these CYP2D6 phenotypes "were not specifically designed to metabolize these drugs but rather are part of a system crucial for the body’s defenses against foreign and potentially dangerous substances," he explained.
Another enzyme that plays a role in drug metabolism is CYP1A2, which is inhibited by many natural substances, including coffee, flavone, quercetin, and corn and is induced by a high-protein diet, constituents of tobacco, charbroiled beef, and cruciferous vegetables.
The enzyme CYP3A4 is also important in drug metabolism. It is inhibited by grapefruit juice, red wine, star fruit, and kava and is induced by St. John’s wort. Drugs metabolized by CYP3A4 include some atypical antipsychotics; some antidepressants; mood stabilizers carbamazepine, gabapentin, and lamotrigine; benzodiazepines; steroids; and statins.
"The bottom line is that we should consider ethnic and individual variations on drug-metabolizing genes such as CYP2D6 PM and UM, and watch out for drug-drug interactions and drug–natural substance interactions," he concluded.
Dr. Lin said he had no relevant financial disclosures.