# Presentation: 722543

## Use of the DILIN Registry and 

**Tissue Bank for Research**

**Paul B. Watkins**
**University of North Carolina**
**Chapel Hill**

**1/28/05**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## SAFE

**SAFE**

**Concept of idiosyncratic **
**  ****hepatocellular injury**

**Not safe**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Resources Created by DILIN

**	****1). Genomic DNA bank.**
**	****2). Immortalized lymphocyte bank.**
**	****3). Registry of subjects.**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Genomic DNA bank:

**Current paradigm:**
**	****DNA samples sent to investigators**

**Future paradigm:**
**	****DNA kept in one location where all **
**	****analyses are performed**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Resources Created by DILIN

**	****1). Genomic DNA bank.**
**	****2). Immortalized lymphocyte bank**
**	****3). Registry of subjects**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Transformed lymphocytes retain inherited transcriptome 

- Studies performed in transformed lymphocytes from CEPH pedigrees.
*Cheung et al, Nature Genetics,33:422, 2003. *
*Morely et al, Nature, 430:732, 2004.*
*Monks et al, Am.J.Hum.Gen. 75:1094, 2004.*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Transformed lymphocytes retain inherited susceptibility to toxicity

**	****5-FU and doxetaxel – **
*Waters et al, PNAS,101:11809, 2004*
**Cisplatin**
**- ***Dolan et al, 64:4353, 2004*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Cancer Res 64:4353, 2004

***Cancer Res 64:4353, 2004***

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Cell based arrays

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Cell based arrays

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Chemotherapy toxicity

- 1). Dose related – intrinsic toxicity?
- 2). Blood is a frequent target organ for 	toxicity.
- 3). In vivo response unknown in CEPH 	pedigrees.

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Resources Created by DILIN

**	****1). Genomic DNA bank.**
**	****2). Immortalized lymphocyte bank.**
**	****3). Registry of subjects.**
**	****	****	**

**- lymphocyte stimulation**
**- “APAP challenge test”**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Lymphocyte stimulation index in patients and controls

*Gut 1997; 41:534-540.*

**Lymphocyte stimulation index in patients and controls**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Duration of a positive SI response

**Duration of a positive SI response**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Slide 15

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Slide 16

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Blood and hepatocyte transcriptome during acetaminophen hepatotoxicity

- NIEHS Toxicogenomics Initiative – rat liver and blood transcriptome changes as a function of dose and time from dose.
- UNC studies:
- 4 gram single oral dose of APAP

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## SAM genes at < 1% FDR for 18hr vs control or 48hr vs control – 211 total genes

- 6 hr	     18 hr	           24 hr	48 hr	     72 hr	       96 hr

*Unpublished data*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Resources Created by DILIN

**	****1). Genomic DNA bank.**
**	****2). Immortalized lymphocyte bank.**
**	****3). Registry of subjects.**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005