Mutagenic Activity and DNA Adduct Formation by 1,2-Epoxy-3-(p-nitrophenoxy)propane, an HIV-1 Protease Inhibitor and GST Substrate

Said, Boctor; Matsumoto, Diane C.; Hamade, Ali; Shank, Ronald C.

doi:10.1006/bbrc.1999.1100

Cited by 2 publications

(1 citation statement)

References 27 publications

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“…Recent studies have demonstrated that GSH and GST reduced the covalent binding of epoxides of well known chemical carcinogens, e.g. aflatoxin B 1 and benzo [a]pyrene, with DNA [301][302][303][304][305]. It has been reported that such DNA-binding was found to be effective in decreasing the hepatocarcinogenesis caused by these compounds [306,307].…”

Section: Glutathione and Other Amino Acids Conjugationmentioning

confidence: 99%

Drug-Metabolizing Enzymes Mechanisms and Functions

Sheweita

2000

CDM

213

128

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Drug-metabolizing enzymes are called mixed-function oxidase or monooxygenase and containing many enzymes including cytochrome P450, cytochrome b5, and NADPH-cytochrome P450 reductase and other components. The hepatic cytochrome P450s (Cyp) are a multigene family of enzymes that play a critical role in the metabolism of many drugs and xenobiotics with each cytochrome isozyme responding differently to exogenous chemicals in terms of its induction and inhibition. For example, Cyp 1A1 is particularly active towards polycyclic aromatic hydrocarbons (PAHs), activating them into reactive intermediates those covalently bind to DNA, a key event in the initiation of carcinogenesis. Likewise, Cyp 1A2 activates a variety of bladder carcinogens, such as aromatic amines and amides. Also, some forms of cytochrome P450 isozymes such as Cyp 3A and 2E1 activate the naturally occurring carcinogens (e.g. aflatoxin B1) and N-nitrosamines respectively into highly mutagenic and carcinogenic agents. The carcinogenic potency of PAHs, and other carcinogens and the extent of binding of their ultimate metabolites to DNA and proteins are correlated with the induction of cytochrome P450 isozymes. Phase II drug-metabolizing enzymes such as glutathione S-transferase, aryl sulfatase and UDP-glucuronyl transferase inactivate chemical carcinogens into less toxic or inactive metabolites. Many drugs change the rate of activation or detoxification of carcinogens by changing the activities of phases I and II drug-metabolizing enzymes. The balance of detoxification and activation reactions depends on the chemical structure of the agents, and is subjected to many variables that are a function of this structure, or genetic background, sex, endocrine status, age, diet, and the presence of other chemicals. It is important to realize that the enzymes involved in carcinogen metabolism are also involved in the metabolism of a variety of substrates, and thus the introduction of specific xenobiotics may change the operating level and the existence of other chemicals. The mechanisms of modification of drug-metabolizing enzyme activities and their role in the activation and detoxification of xenobiotics and carcinogens have been discussed in the text.

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