Xenobiotic metabolism oxidation

Apart from monooxygenases, other enzymes concerned wih xenobiotic metabolism may also be induced. Some examples are given in Table 2.5. Induction of glucuronyl transferases is a common response and is associated with phenobarbital-type induction of CYP family 2. Glutathione transferase induction is also associated with this. A variety of compounds, including epoxides such as stilbene oxide and... 

Metabolism - a final factor in need of comparative studies is the metabolism of xenobiotics. One obvious difference between mammalian and fish species is that their bodies usually function at temperatures at least 10°C different. This fact undoubtedly explains some differences in metabolic rate but even when in vitro incubations are run at optimal temperatures there is a 10 - 100 fold higher rate of mammalian vs. fish metabolism (14, 15). In other words, the level of the xenobiotic-metabolizing capacity, especially for oxidative pathways, of the poikilothermic animals is considerably lower than that of the homeothermic species. Elsewhere in this volume Dr. Bend has focused on this aspect of the handling of xenobiotics by fish (16). 

Whereas most, if not all, of the enzymes involved in xenobiotic metabolism can form reactive metabolites (Table 8.1), the enzyme systems most frequently involved in the activation of xenobiotics are those which catalyze oxidation reactions. The cytochrome P450 monooxygenases (CYP) are by far the most important enzymes involved in the oxidation of xenobiotics. This is because of the abundance of CYP (especially in the liver), the numerous isozymes of CYP, and the ability of CYP to be induced by xenobiotic compounds. 

Other Hormones. Pituitary hormones regulate the function of many other endocrine glands, and hypophysectomy in male rats results in a decrease in the activity of xenobiotic metabolizing enzymes. Administration of adrenocorticotropic hormone (ACTH) also results in a decrease of those oxidative enzyme activities that are gender dependent. In contrast, ACTH treatment of female rats causes an increase in aminopyrine /V-dcmcthylasc but no change in other activities. 

The addition of H20 to epoxide rings, a process called epoxide hydration, is important in the metabolism of some xenobiotic materials. This reaction can occur, for example, with benzo(a)pyrene 7,8-epoxide, formed by the metabolic oxidation of benzo(a)pyrene, as shown in Figure 7.3. Hydration of an epoxide group on a ring leads to the trans dihydrodiols in which the -OH groups are on opposite sides of the ring. 

Figure 7.4 Metabolic oxidation of nitrogen, phosphorus, and sulfur in xenobiotic compounds.

Nutritional and nutritional status markedly influence xenobiotic metabolism in laboratory animals. Microsomes were prepared from the livers of rats which had been fed chow or modified AIN-76 diets with or without oxidized or unoxidized sulfur amino acids for 7 days. The pattern of benzo(a)pyrene (BaP) metabolites formed by each microsomal preparation in the presence of a NADPH-generating system was determined using high performance liquid chromatography (HPLC). The results indicate that oxidized sulfur amino acids induce different forms of cytochromes P-450 in rat liver Which are reflected by different BaP metabolic profiles. 

Fig. 3.2 Biological abstraction. Yeast cells reflect anaerobic, reductive metabolism (intestine) as well as aerobic, oxidative metabolism (liver), if glycolysis is regarded as the most active pathway. Therefore, the yeast Saccharomyces cerevisiae is a good model organism for studies of xenobiotic metabolism.

Examples of oxidative reactions are shown in Table 3.3. Generally, reduction and hydrolysis reactions play subordinate roles in xenobiotic metabolism compared to oxidation reactions. Examples of reduction and hydrolysis reactions are shown in Tables 3.4 and 3.5, respectively. To reiterate the net result of phase I reactions is the... 

In addition to DNA adducts that occur as a result of covalent binding of reactive intermediates generated by oxidation or conjugation of parent compounds to DNA, reactive oxygen species produced during xenobiotic metabolism can also react with nucleophilic biomolecules. 

Figure 20.9. Protective and toxic signal balance in xenobiotic metabolism and generation of oxidative stress.

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