Biology of Disease

glucuronyl transferase

R-OH + UDP-glucuronate R-O-glucuronate + UDP

sulfotransferase

R-OH + PAPS R-O-SO 3 – + PAP

The increased water solubility of the products facilitates their excretion by the

kidneys, although small amounts are also lost in bile to the feces.

It is unfortunately the case that a number of poisons are rendered more toxic

by oxidation by the P-450 system. Indeed, a number of fat-soluble compounds

that are relatively harmless because they would normally accumulate in

adipose tissue are converted into potentially lethal materials because of the

increase in water solubility. Thus, a number of indirectly acting carcinogens,

for example, benzo[a]pyrene, found in cigarette smoke and the toxin aflatoxin

B1 from Aspergillus flavus, are converted to highly carcinogenic products

(Figure 12.4 (A)and(B)).

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W^dad\nd[Y^hZVhZ

Figure 12.4 The oxidation of (A) benzo [a] pyrene and (B) aflatoxin by the cytochrome P-450 system to reactive chemicals that can bind with guanine

bases of DNA and so induce carcinogenesis.

X]VeiZg&'/ TOXICOLOGY

('% W^dad\nd[Y^hZVhZ

A) B)

O

N

N

N

HN

H 2 N

O

+

OH

OH

OH

OH

OH

Cytochrome P-450

oxidation

Carcinogenic

diol-epoxide product

Binding of diol-epoxide

to a guanine base

of DNA

DNA

Benzo[a]pyrene

N

N

N

HN

H 2 N

O

O

O

OCH 3

O

O

O

OCH 3

O

O

O

O

OCH 3

O

O

O

O

O

O

O

+

Aflatoxin

Cytochrome P-450

oxidation

Carcinogenic

epoxide

product

Binding of epoxide

to a guanine

base of DNA

DNA

HO

DNA