Looking beneath the surface of the CYP3A5 polymorphism

In this issue of Pediatric Transplantation, Ferraresso et al. (1) report on the effect of CYP3A5 polymorphisms in adolescent kidney transplant patients. At first glance, this appears to be another retelling of an old story. However, on further inspection the manuscript provides an important lesson about what we know and what we do not know about gene polymorphisms and the effect of drug therapy. What is apparent is that tacrolimus is metabolized primarily by the cytochrome P450 3A family of enzymes. The main enzymes of interest are CYP3A4 and CYP3A5. The genetic variants of CYP3A4 are rare in Caucasians, and have not been useful in describing changes in drug metabolism. CYP3A5 is of more interest in that the *3 allele has an insertion that encodes for a stop codon (2). Therefore, the protein is truncated and non-functional. The patient who is a *3/*3 nonexpressor of CYP3A5 may have both increased tacrolimus absorption, because of decreased metabolism in the gastrointestinal tract, and decreased drug elimination because of lower hepatic metabolism. Therefore, there are two processes that increase the tacrolimus blood concentrations in a CYP3A5 *3/*3 non-expressor. The first observation that the CYP3A5 polymorphism may affect dose-adjusted tacrolimus levels was made in pediatric heart transplant patients (3, 4). Following these reports, no less than 20 publications have followed in every type of transplantation and in many differing ethnic/ racial transplant patient groups. So the fact that CYP3A5 enzyme expressors have to receive larger doses, on average, than CYP3A5 *3/*3 non-expressors to achieve therapeutic blood concentrations is well established. The problem with this association is that it is on average ; approximately 50% of all CYP3A5 *3/*3 patients have a tacrolimus level/dose that is the same as the CYP3A5 *1/*3 or *1/*1 enzyme expressors (5). Therefore, genotyping for CYP3A5 pretransplant gives you as much chance of predicting their tacrolimus dosage requirement as flipping a coin. Authors have struggled to give this polymorphism significance (6), but the fact is that we can measure tacrolimus blood concentrations easily and make dosage adjustments on that basis. After all, we are only interested in the genotype if it gives us clear insight into the phenotype. That is, however, not the end of the story, as Ferraresso and colleagues taught us. The CYP enzymes are involved in the metabolism of both endogenous substances and xenobiotics, and have complex patterns of evolution. In this paper, Ferraresso and colleagues point out that CYP3A5 has been tied to blood pressure regulation. This association is of particular importance in Africans and African-Americans, who have a much higher frequency of the CYP3A5 *1 allele. CYP3A5 is present in kidney, and converts cortisol to 6b-hydroxycortisol and corticosterone to 6b-hydroxycorticosterone which lead to sodium retention. The evolutionary nature of racial differences in CYP3A5 expression may be due to climate and the need to retain water (7). Two previous publications have examined CYP3A5 polymorphisms in African-Americans, and have concluded that the *1 allele is a risk factor for hypertension (8, 9). The report of Ferraresso and colleagues deals with Caucasian subjects and a small number of CYP3A5 expressors, so it is not surprising that no significant differences were found in blood pressure between the expressors and non-expressors. The observation that the CYP3A5 expressors required more anti-hypertensive medication is of interest, and additional follow up is needed in larger and more racially diverse populations. This is not the first example of looking only at the surface of what we understand when assessing the impact of gene polymorphisms in Pediatr Transplantation 2007: 11: 239–240 Copyright 2007 Blackwell Munksgaard