Glutathione dependent bioactivation

Anders MW. Glutathione-dependent bioactivation of haloalkanes and hataalkenes. Drug Metab Rev 2004 36(3-4) 583-594. 

Dekant W, Vamvakas S. Glutathione-dependent bioactivation of xenobiotics. Xenobiotica 1993 23 873-887. 

CAPEN, C.C. (1996) Toxic responses of the endocrine system. In Cassarett and Doull s Toxicology, The Basic Science of Toxicology, edited by C.D.Klaassen, 5th edition (New York McGrawHill). COULSON, C.J. (1994) Molecular Mechanisms of Drug Action, (London Taylor Francis). DEKANT, W. and VAMVAKAS, S. (1993) Glutathione-dependent bioactivation of xenobiotics. 

Patel, N., Bimer, G, Dekant, W. Anders, M.W. (1994) Glutathione-dependent biosynthesis and bioactivation of, S -(l,2-dichlorovinyl)glutathionc and. S -(1,2-dichlorovinyl)-i,-cysteine, the glutathione and cysteine S-conjugates of dichloroacetylene, in rat tissues and subcellular fractions. Drug Metab. Dispos., 22, 143-147... 

Knowles and Milner, 2000). Furthermore, these compounds are thought to be involved in the inhibition of certain cytochrome P-450 enzyme-dependent bioactivations of procarcinogens and protoxicants (Brady et al., 1991), as well as to increase levels of glutathione-S-transferase (GST), an enzyme of particular importance in the detoxification of xenobiotics in the body (Wilce and Parker, 1994). Most recently, the ability of various plants and plant extracts to influence apoptosis, or programmed cell death, in cancerous cells in an attempt to arrest their proliferation, has been the topic of much research. Allicin has been shown to induce apoptosis in a variety of cell lines, including human hepatocellular carcinoma cells (KIM-1) and human lymphoid leukemia (MOLT-4B) cells (Thatte et al., 2000). 

Amodiaquine is bioactivated by CYP2C8 to N-desethyl-amodiaquine (DEAQ) which concentrates in blood cells [3 ]. DEAQ, similar to chloroquine, inhibits the digestion of haemoglobin and inhibits glutathione-dependent destruction of ferriprotoporphyrin IX, causing toxicity due to accumulation of the peptide [4 ,5 ]. 

Dekant W, Martens G, Vamvakas S, et al. 1987. Bioactivation of tetrachloroethylene. Role of glutathione S-transferase-catalyzed conjugation versus cytochrome P-450-dependent phospholipid alkylation. Drug Metab Dispos Biol Fate Chem 15 702-709. 

No studies were located indicating that any populations are unusually susceptible to heptachlor or heptachlor epoxide. There is a possibility that very young children may exhibit particular susceptibility to hepatic effects because of the immaturity of the hepatic microsomal system. Heptachlor is bioactivated to produce heptachlor epoxide which is more toxic than heptachlor. Preadolescent children have a greater rate of glutathione turnover, and they are expected to be more susceptible to heptachlor epoxide-induced toxicity. Their susceptibility would probably depend upon their ability to detoxify heptachlor epoxide. Individuals who show reduced liver function for other... 

Primary hepatocytes from rats, mice, hamsters, rabbits, dogs, pigs, monkeys, and humans have been shown to be susceptible to acetaminophen in vitro. The cytotoxicity of acetaminophen varies considerably depending on species, presumably due to differences in bioactivation and glutathione status. The most obvious morphological effect of acetaminophen in isolated primary hepatocytes is blebbing of the cell membrane. However, electron microscopy has shown that toxicity is associated with progressive... 

In humans, the bioactivation of tienilic acid as its reactive intermediate depends on cytochrome P-450 2C9. This isoform is one of the major forms of cytochrome P-450 in the human liver. It has recently been demonstrated that in the presence of cytochrome P-450 thiophene is oxidized in vivo to yield thiophene sulfoxide (Fig. 32.12). This unusual function is a very electrophilic species capable of reacting with thiol group nucleophiles such as glutathione (detoxication) or proteins. This interaction with free proteins that contain thiol groups may give rise to an adduct and the potential associated toxicity. 

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