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Hodgson E. Modern toxicology [2004].pdf
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158 REACTIVE METABOLITES

2-AAFis correlated with the ability of the organism to sequentially produce theN - hydroxylated metabolite followed by the sulfate ester. Therefore in an animal such as the guinea pig, which does not produce theN -hydroxylatedmetabolite,2-AAFis not carcinogenic. In contrast, both male and female rats produce theN -hydroxylatedmetabolite, but only male rats have high rates of tumor formation. This is because male rats have up to10-foldgreater expression of sulfotransferase 1C1 than female rats, which has been implicated in the sulfate conjugation of2-AAFresulting in higher production of the carcinogenic metabolite.

8.6.7Benzo(a)pyrene

The polycyclic aromatic hydrocarbons are a group of chemicals consisting of two or more condensed aromatic rings that are formed primarily from incomplete combustion of organic materials including wood, coal, mineral oil, motor vehicle exhaust, and cigarette smoke. Early studies of cancer in the 1920s involving the fractionation of coal tar identified the carcinogenic potency of pure polycyclic aromatic hydrocarbons, including dibenz(a,h)anthracene and benzo(a)pyrene. Although several hundred different polycyclic aromatic hydrocarbons are known, environmental monitoring usually only detects a few compounds, one of the most important of which is benzo(a)pyrene. Benzo(a)pyrene is also one of the most prevalent polycyclic aromatic hydrocarbons found in cigarette smoke.

Extensive studies of metabolism of benzo(a)pyrene have identified at least 15 phase I metabolites. The majority of these are the result of CYP1A1 and epoxide hydrolase reactions. Many of these metabolites are further metabolized by phase II enzymes to produce numerous different metabolites. Studies examining the carcinogenicity of this compound have identified the7,8-oxideand7,8-dihydrodiolas proximate carcinogens and the7,8-diol-9,10epoxide as a strong mutagen and ultimate carcinogen. Because of the stereoselective metabolizing abilities of CYP isoforms, the reactive7,8-diol-9,10-epoxide can appear as four different isomers. (Figure 8.5). Interestingly only one of theseisomers(+)-benzo(a)pyrene7,8-diol-9,10epoxide-2has significant carcinogenic potential. Comparative studies with several other polycyclic aromatic hydrocarbons have demonstrated that only those substances that are epoxidized in the bay region of the ring system possess carcinogenic properties.

8.6.8Acetaminophen

A good example of the importance of tissue availability of the conjugating chemical is found with acetaminophen. At normal therapeutic doses, acetaminophen is safe, but can be hepatotoxic at high doses. The major portion of acetaminophen is conjugated with either sulfate or glucuronic acid to form water-soluble,readily excreted metabolites and only small amounts of the reactive intermediate, believed to be quinoneimine, are formed by the CYP enzymes (Figure 8.6).

When therapeutic doses of acetaminophen are ingested, the small amount of reactive intermediate forms is efficiently deactivated by conjugation with glutathione. When large doses are ingested, however, the sulfate and glucuronide cofactors (PAPS and UDPGA) become depleted, resulting in more of the acetaminophen being metabolized to the reactive intermediate.

EXAMPLES OF ACTIVATING REACTIONS

159

 

O

Benzo(a)pyrene

7,8 epoxide of benzo(a)pyrene

O

HO

 

OH

 

HO

 

OH

O

7,8 dihydrodiol of benzo(a)pyrene

HO

OH

7,8-diol-9,10-epoxidesof benozo(a)pyrene

Figure 8.5 Selected stages of biotransformation of benzo(a)pyrene. The diol epoxide can exist in four diastereoisomeric forms of which the key carcinogenic metabolite is(+)-benzo(a)pyrene7,8-diol-9,10-epoxide.

As long as glutathione (GSH) is available, most of the reactive intermediate can be detoxified. When the concentration of GSH in the liver also becomes depleted, however, covalent binding to sulfhydryl (-SH)groups of various cellular proteins increases, resulting in hepatic necrosis. If sufficiently large amounts of acetaminophen are ingested, as in drug overdoses and suicide attempts, extensive liver damage and death may result.

8.6.9Cycasin

When flour from the cycad nut, which is used extensively among residents of South Pacific Islands, is fed to rats, it leads to cancers of the liver, kidney, and digestive tract. The active compound in cycasin is the β-glucosideof methylazoxymethanol (Figure 8.7). If this compound is injected intraperitoneally rather than given orally, or if the compound is fed togerm-freerats, no tumors occur. Intestinal microflora possess the necessary enzyme,β-glucosidase,to form the active compound methylazoxymethanol, which is then absorbed into the body. The parent compound, cycasin, is carcinogenic only if administered orally becauseβ-glucosidasesare not present in mammalian tissues but are present in the gut. However, it can be demonstrated that the metabolite, methylazoxymethanol, will lead to tumors in both normal andgerm-freeanimals regardless of the route of administration.