Editorial

Looking beneath the surface of the CYP3A5polymorphism

In this issue of Pediatric Transplantation, Ferra-resso et al. (1) report on the effect of CYP3A5polymorphisms in adolescent kidney transplantpatients. At first glance, this appears to beanother retelling of an old story. However, onfurther inspection the manuscript provides animportant lesson about what we know and whatwe do not know about gene polymorphisms andthe effect of drug therapy.What is apparent is that tacrolimus is meta-

bolized primarily by the cytochrome P450 3Afamily of enzymes. The main enzymes of interestare CYP3A4 and CYP3A5. The genetic variantsof CYP3A4 are rare in Caucasians, and have notbeen useful in describing changes in drug meta-bolism. CYP3A5 is of more interest in that the *3allele has an insertion that encodes for a stopcodon (2). Therefore, the protein is truncated andnon-functional. The patient who is a *3/*3 non-expressor of CYP3A5 may have both increasedtacrolimus absorption, because of decreasedmetabolism in the gastrointestinal tract, anddecreased drug elimination because of lowerhepatic metabolism. Therefore, there aretwo processes that increase the tacrolimusblood concentrations in a CYP3A5 *3/*3non-expressor.The first observation that the CYP3A5 poly-

morphism may affect dose-adjusted tacrolimuslevels was made in pediatric heart transplantpatients (3, 4). Following these reports, no lessthan 20 publications have followed in every typeof transplantation and in many differing ethnic/racial transplant patient groups. So the fact thatCYP3A5 enzyme expressors have to receivelarger doses, on average, than CYP3A5 *3/*3non-expressors to achieve therapeutic bloodconcentrations is well established. The problemwith this association is that it is ��on average��;approximately 50% of all CYP3A5 *3/*3patients have a tacrolimus level/dose that is thesame as the CYP3A5 *1/*3 or *1/*1 enzyme

expressors (5). Therefore, genotyping forCYP3A5 pretransplant gives you as much chanceof predicting their tacrolimus dosage requirementas flipping a coin. Authors have struggled to givethis polymorphism significance (6), but the fact isthat we can measure tacrolimus blood concen-trations easily and make dosage adjustments onthat basis. After all, we are only interested in thegenotype if it gives us clear insight into thephenotype.That is, however, not the end of the story, as

Ferraresso and colleagues taught us. The CYPenzymes are involved in the metabolism of bothendogenous substances and xenobiotics, andhave complex patterns of evolution. In thispaper, Ferraresso and colleagues point out thatCYP3A5 has been tied to blood pressure regu-lation. This association is of particular import-ance in Africans and African-Americans, whohave a much higher frequency of the CYP3A5 *1allele. CYP3A5 is present in kidney, and convertscortisol to 6b-hydroxycortisol and corticosteroneto 6b-hydroxycorticosterone which lead to so-dium retention. The evolutionary nature of racialdifferences in CYP3A5 expression may be due toclimate and the need to retain water (7). Twoprevious publications have examined CYP3A5polymorphisms in African-Americans, and haveconcluded that the *1 allele is a risk factor forhypertension (8, 9). The report of Ferraresso andcolleagues deals with Caucasian subjects and asmall number of CYP3A5 expressors, so it is notsurprising that no significant differences werefound in blood pressure between the expressorsand non-expressors. The observation that theCYP3A5 expressors required more anti-hyper-tensive medication is of interest, and additionalfollow up is needed in larger and more raciallydiverse populations.This is not the first example of looking only at

the surface of what we understand whenassessing the impact of gene polymorphisms in

Pediatr Transplantation 2007: 11: 239–240 Copyright � 2007 Blackwell Munksgaard

Pediatric TransplantationDOI: 10.1111/j.1399-3046.2007.00688.x

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transplant patients. An additional example isthat of ABCB1 which encodes for the productionof the membrane transporter P-glycoprotein. P-glycoprotein is involved in inhibiting the absorp-tion of P-glycoprotein substrates such as tacrol-imus, and most transplant studies have focusedonly on the absorption of tacrolimus in relationto ABCB1 genotypes. The effect of ABCB1haplotypes on tacrolimus absorption is secon-dary to CYP3A5, and can only be seen inCYP3A5 non-expressors (10). However, individ-ual studies have broadly examined the impact ofABCB1 genotypes, and have shown them to beassociated with persistent acute rejection in lungtransplantation (11), biopsy-proven acute rejec-tion in kidney transplantation (12), osteonecrosis(13), calcineurin-associated nephrotoxicity (14),tacrolimus neurotoxicity (15) and gingival hyper-plasia (16).Therefore, Ferraresso and colleagues have

provided little new information on CYP3A5polymorphisms and tacrolimus dosing, and nonew information on these polymorphisms andtacrolimus pharmacokinetics. Their suggestionthat CYP3A5 genotyping be performed prior totransplantation in all patients is not presentlysupportable. However, if their report stimulatesstudies which eventually allow us to identifypatients at high risk for the development of drug-resistant hypertension after transplantation, thenall transplant patients will have benefited fromtheir report.

Gilbert J. Burckart

Professor of Pharmacy, University of Southern California,

Los Angeles, CA, USA.

Tel.: +1 323 442 2252

Fax: +1 323 442 2250

E-mail: burckart@usc.edu

References

1. Ferrarresso M, Tirelli A, Grillo P, Martina V, Edefonte

A. Influence of Cyp3a5 genotype on tacrolimus pharmacoki-

netics and pharmacodynamics in young kidney transplant

recipients. Pediatr Transplant 2006, Doi: 10.1111/j.1399-

3046.2006.00688.

2. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A

promoters and characterization of the genetic basis of poly-

morphic CYP3A5 expression. Nat Genet 2001: 27: 383–391.

3. Zheng H, Webber S, Schuetz E, et al. Cytochrome P4503A

and TNF-a genotypes are associated with tacrolimus dosing in

pediatric heart transplant patients. Hum Immunol 2002: 63

(Suppl. 1): S15.

4. Zheng H, Webber S, Zeevi A, et al. Tacrolimus dosing in

pediatric heart transplant patients is related to CYP3A5 and

MDR1 gene polymorphisms. Am JTransplant 2003: 3: 477–483.

5. Burckart GJ, Liu XI. Pharmacogenetics in transplant

patients: Can it predict pharmacokinetics and pharmacody-

namics? Ther Drug Monit 2006: 28: 23–30.

6. MacPhee IA, Fredericks S, Tai T, et al. The influence of

pharmacogenetics on the time to achieve target tacrolimus

concentrations after kidney transplantation [see comment]. Am

J Transplant 2004: 4: 914–919.

7. Thompson EE, Kuttab-Boulos H, Witonsky D, et al.

CYP3A variation and the evolution of salt-sensitivity variants.

Am J Hum Genet 2004: 75: 1059–1069.

8. Givens RC, Lin YS, Dowling AL, et al. CYP3A5 genotype

predicts renal CYP3A activity and blood pressure in healthy

adults. J Appl Physiol 2003: 95: 1297–1300.

9. Ho H, Pinto A, Hall SD, et al. Association between the

CYP3A5 genotype and blood pressure. Hypertension 2005: 45:

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10. Wang J, Zeevi A, McCurry K, et al. Impact of ABCB1

(MDR1) haplotypes on tacrolimus dosing in adult lung trans-

plant patients who are CYP3A5 *3/*3 nonexpressors. Transpl

Immunol 2006: 15: 235–240.

11. Zheng HX, Zeevi A, McCurry K, et al. The impact of

pharmacogenomic factors on acute persistent rejection in adult

lung transplant patients. Transpl Immunol 2005: 14: 37–42.

12. Grinyo J, Vanrenterghem Y, Nashan B, et al. Association

of three polymorphisms with acute rejection after kidney

transplantation: An exploratory pharmacogenetic analysis of a

randomized multicenter clinical trial (the Caesar Study).

Transplantation 2006: 82 (Suppl. 3): 410–411.

13. Asano T, Takahashi KA, Fujioka M, et al. ABCB1 C3435T

and G2677T/A polymorphism decreased the risk for steroid-

induced osteonecrosis of the femoral head after kidney trans-

plantation. Pharmacogenetics 2003: 13: 675–682.

14. Hauser IA, Schaeffeler E, Gauer S, et al. ABCB1 genotype

of the donor but not of the recipient is a major risk factor for

cyclosporine-related nephrotoxicity after renal transplantation.

J Am Soc Nephrol 2005: 16: 1501–1511.

15. Yamauchi A, Ieiri I, Kataoka Y, et al. Neurotoxicity induced

by tacrolimus after liver transplantation: Relation to genetic

polymorphisms of the ABCB1 (MDR1) gene. Transplantation

2002: 74: 571–572.

16. Meisel P, Giebel J, Kunert-Keil C, et al. MDR1 gene

polymorphisms and risk of gingival hyperplasia induced by

calcium antagonists. Clin Pharmacol Ther 2006: 79: 62–71.

Editorial

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