Genetic flaw stymies drug impact

Doctors have long known that people differ in the way theirbodies respond to a given drug. The same medicine in the same dosemay work wonders in one patient but do nothing for the next.

Now an international team of researchers has traced some ofthese differences to a genetic defect that turns out to be one of themost widespread hereditary disorders known. Between 35 percent and43 percent of white people carry one of the two genes needed tosuffer from the defect, and from 5 percent to 10 percent have both.Figures for blacks have not been obtained.

Reporting in last week's Nature, the research team's leader,Frank J. Gonzalez of the National Cancer Institute, said the defectinvolves an enzyme called cytochrome p450. It is well-known thatcells make this enzyme to protect themselves against toxic chemicals.Enzyme p450 chemically modifies a wide range of toxins into a formthat is harmless.

Cells also process drugs as foreign substances that could betoxic. As it happens, the medically useful form of some drugs is notthe form in which it is taken but the form into which p450 modifiesit. Thus, people who have faulty p450 enzymes will be unable toconvert their medicine into its useful form.

Whether a person has the proper form of p450 depends on thegenes in each cell. The genes determine the structure of the enzymethat will be manufactured within the cell.

As is the case with most genes, every cell carries two versions,one inherited from each parent. If one gene is defective and leadsto the manufacture of a useless form of p450, the person may still befine because the other copy of the gene is good. The good gene inthis case is said to be dominant and the bad gene recessive. Theperson suffers only if both p450 genes are bad, because there is nogood gene to make the proper enzyme.

Gonzalez and his colleagues said people with at least one goodgene for p450 can metabolize drugs, such as the high blood pressuremedicine called debrisoquine, up to 200 times more efficiently thanthose who lack a good p450 gene but take the same dose.