Activation/Detoxication

Non-polar(lipophilic)

Hydrophobic

Lipophobic Hydrophilic(Polar)

XENOBIOTIC

INTERMEDIATE METABOLITE

ELIMINATION

WATER-SOLUBLE METABOLITE

May be reactive/toxic

Can accumulate in tissues

Phase I MetabolismOxidation

Phase II Metabolism

ConjugationSol

ubili

ty in

lipi

ds

Sol

ubili

ty in

wat

er

1

2

3

4

56

78

9

1 0

1 1

1 2

H

3 - O H

3 , 6 - Q u i n o n e

[ 6 - O H ]

6 , 1 2 - Q u i n o n e

1 - O H

1 , 6 - Q u i n o n e

9 , 1 0 - O x i d e

7 , 8 - O x i d e

7 , 8 - d h d o

7 , 8 - d i o l - 9 , 1 0 - o x i d e

t e t r o l

a d d u c t s

9 , 1 0 - d h d o

4 , 5 - d h d o

9 - O H

O H

O H

O H

O

O

O

O

O

O

O

H

H

O

H

O H

H

H

H O

O HH

H

H O

O HH

OH

H

ultimate active metabolite BPDE

proximate metabolites

METABOLIC SCHEME OF BENZO[a]PYRENE

(BP, B[a]P)

O

OOH

HO

7,8-Quinone7,8-catechol

OH O-Glucuronide

OOH

HH OH

S-GlutathioneHH OH

O

H

HO

HOH

Glutathione conjugate

The main purpose of this pilot study is to identify an optimal concentration of diesel exhaust which can be used to study the risks of cardiac changes in healthy older subjects. Results from this study may increase the understanding of how gaseous and particulate air pollutants (which causes the haze seen in some polluted cities) may adversely affect the functioning of the human cardiovascular and respiratory systems. This pilot research will study the responses to diesel exhaust in healthy older subjects with the specific GSTM1 and GSTP1 genotype. For more information, please visit our web site at www.epastudies.org or call Westat EPA Recruiting at 966-0604. Approved June 08, 2007 by the Committee on the Protection of the Rights of Human Subjects Biomedical Institutional Review Board. IRB # 07-0190 (GCRC #2579). This email is sponsored by: U.S. Environmental Protection Agency Human Studies Division located on the UNC-Chapel Hill campus. This email is sponsored by: U.S. Environmental Protection Agency Human Studies Division This email is sponsored by: CEMALB

Another exampleOrganophosphate Insecticides:

• Parathion

• Malathion

Parathion

Malathion

Hydrolysis enzymes

• Serum cholinesterase BChE

• Serum paraoxonase PON1

• Polymorphisms in PON1 – differential sensitivity

Heart diseaseAtherosclerosis Gulf War Syndrome

Effect is the outcome of interaction between susceptibility and

exposure

Target organs

• What makes a particular organ a target for toxicity / infection ?

• What makes a particular organ or species susceptible ?

Portal of entry to Blood to Target Organ

e.g. Intestine to hepatic portal vein to liver to vena cava to heart to lungs back to heart to aorta to rest of body

Location, location, location

Intestines

Hepatic portal veinLiver

Vena cava Aorta

Lungs

Gut flora

• Reductions– nitro to amine

• Hydrolyses– Cleavage of glucuronides

NO NOHNO2 NHH H

Reaction

OHo o

OH

HO

OH

COOH

Glucuronidation

Reaction

OHo o

O H

H O

O H

C O O H

De-glucuronidation-glucuronidase

Aglycone Conjugate

Enterohepatic recirculation(EHC)

Liver

Intestine

• Presence/absence of receptors– Estrogen receptors, Ah receptor

• Presence/absence of transporters/carriers– Resistance to chemotherapy

• Presence of repair mechanisms– DNA repair

• Balance of metabolic activation/detoxication

Factors affecting xenobiotic metabolism

• Intrinsic– Species, strain, gender, age, genotype

• Physiological status– Temperature, time of day, season, – Health status, disease, stress– Diet, nutritional status

• Related to exposure– Route of administration, frequency and size of

dose, co-exposures (induction, inhibition)

Genetic polymorphisms

• CYP2D6 Debrisoquine hydroxylation (poor and extensive metabolizers)

• Acetylation (fast and slow acetylators)

• GSTM null genotype

Changes in P450 levels with ageRats

2A1

2C6

3A2

M: 2C6, 2C11, 3A2

F: 2A1, 2C6, 2C12

Cross-species extrapolation

• What factors are similar ?

• What factors are different ?

The basic problem: data determined in experimental animals

Information needed about target species (usually humans)

Genetic Toxicology

Reading material:

Casarett and Doull Chapter 9,

Timbrell, Chapter 6, pp. 259-279