# Presentation: 724630

## TPMT Pharmacogenetics

**TPMT Pharmacogenetics**

**Richard Weinshilboum, M.D.**
**Department of Molecular Pharmacology and Experimental Therapeutics**
**Mayo Medical School-Mayo Clinic**
**Rochester, MN**

## Thiopurines and Natural Purines

**Thiopurines and Natural Purines**

_**6-Mercaptopurine**_

_**Hypoxanthine**_

_**6-Thioguanine**_

_**Guanine**_

## Pharmacogenetics

**Pharmacogenetics**

**The study of the role of inheritance in individual variation in response to xenobiotics, including drugs.**

## Pharmacogenetic“Targets”

**Pharmacogenetic****“Targets”**

**Drug absorption**
**Drug distribution**
**Drug-receptor interaction**
**Drug metabolism**
**Drug excretion**

## Metabolism of 6-Mercaptopurine

**Metabolism of 6-Mercaptopurine**

**Xanthine Oxidase**
**(XO)**

**Thiopurine**
**Methyltransferase**
**(TPMT)**

**XO**

**TPMT**

**2,8-Dihydroxy-6-Methylmercaptopurine**

**AdoHcy**

**AdoHcy**

**AdoMet**

**AdoMet**

## TPMT Catalyzed Methylation of 6-MP

**TPMT Catalyzed Methylation of 6-MP**

_**TPMT**_

**AdoMet**

**AdoHcy**

_**6-Mercaptopurine**_

_**6-Methylmercaptopurine**_

## Human RBC TPMT

**Human RBC TPMT**

***TPMT******H******/TPMT******H***

***TPMT******L******/TPMT******H***

***TPMT******L******/TPMT******L***

## Thiopurine Metabolism

**Thiopurine Metabolism**

**TPMT**

## TPMT in ALL

**TPMT in ALL**

**Units TPMT/ml RBCs**

**pmol 6-TGN/8 x 10****8**** RBCs**

## Slide 10

## Max. 27.2

**Lancet 341:436, Feb 13, 1993**

**WBC (10****6**** /mL)**

**Days after transplantation**

**0****	****10****	****20****	****30****	****40****	****50****	****60****	****70****	****80****	****90****	****100**

**WBC**

**Azathioprine**

**200**

**AZA (mg/day)**

**300**

**100**

**0**

**Max. 27.2**

## TPMTGenetic PolymorphismClinical Consequences

**TPMT****Genetic Polymorphism****Clinical Consequences**

**Low TPMT**
**Increased thiopurine toxicity**
**Increased risk for secondary neoplasm**
**High TPMT**
**Decreased therapeutic effect**

## TPMT PharmacogeneticsClinical Lessons

**TPMT Pharmacogenetics****Clinical Lessons**

**Intermediate phenotype**
**Association with clinical trials**

## Pharmacogenomics

**Pharmacogenomics**

**The convergence of advances in pharmacogenetics and human genomics**

## Selected Human TPMT Alleles

**Selected Human TPMT Alleles**

## Human TPMT ProteinRRL Degradation

**Human TPMT Protein****RRL Degradation**

**Time, hours**

**TPMT Protein**
**% Remaining**

## SNPsNonsynonymous

**SNPs****Nonsynonymous**

**Common -- often functionally significant**
**Most often -- reduce protein quantity**
**Mechanism -- most often accelerated degradation**

## Human RBC TPMT

**Human RBC TPMT**

**25**

**20**

**15**

**10**

**5**

**0**

**0**

**5**

**10**

**15**

**20**

**25**

**Percentage**

**TPMT Activity,**

**Units/ml RBC**

**Korean Children**

**N = 309**

## Human TPMT Genetic Polymorphism

**Human TPMT ****Genetic Polymorphism**

***Collie-Dugid et al., Pharmacogenetics **_**9**_**:37-42, 1999**

## Human RBC TPMT

**Human RBC TPMT**

***TPMT******H******/TPMT******H***

***TPMT******L******/TPMT******H***

***TPMT******L******/TPMT******L***

## Molecular PharmacogeneticsPrinciples

**Molecular Pharmacogenetics****Principles**

**Allelic heterogeneity**
**Ethnic variation in allele frequencies**

## Human TPMT Gene

**Human TPMT Gene**

## TPMT VNTR

**TPMT VNTR**

## TPMT VNTR“High” Group

***TPMT***** VNTR****“High” Group**

**RBC TPMT Activity**
**U/ml RBCs**

## % of Subjects Per 

**0**

**5**

**10**

**15**

**20**

**0**

**5**

**10**

**Human **

**RBC**

** **

**TPMT**

**298 Unrelated Adults**

**G460A**

**A719G**

***TPMT*1***

***TPMT*3A***

**Selected Human **

***TPMT***

** ****Alleles**

**Ala154Thr**

**Tyr240Cys**

**(wild type)**

**TPMT**

** **

**Pharmacogenetics**

**(A)**

**(B)**

**% of Subjects Per **
**0.5 Units of Activity**