K region benzo(α)pyrene-4,5-oxide is conjugated by homogeneous gluthathione S-transferases

Nemoto, Nobuo; Gelboin, Harry V.; Habig, William H.; Ketley, Jeanne N.; Jakoby, William B.

doi:10.1038/255512a0

Cited by 86 publications

(16 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…None of the human transferases was effective with the alkyl epoxide, 1,2-epoxy-3-(p-nitrophenoxy)-propane, although the K-region epoxide, benzo[a]-pyrene 4,5-oxide, has been shown to serve as a substrate [20].…”

Section: Specificitymentioning

confidence: 99%

Multiple Forms of Human Glutathione S‐Transferase and Their Affinity for Bilirubin

Kamisaka¹,

Habig²,

Ketley³

et al. 1975

European Journal of Biochemistry

Self Cite

275

112

View full text Add to dashboard Cite

The initial enzymic step in mercapturic acid formation is catalyzed by glutathione S-transferase.Several species of this enzyme, designated as transferases a, p, y, 6 and E on the basis of increasing isoelectric points, were isolated from human liver. Evidence is presented that each of the purified species is homogeneous with respect to sodium dodecylsulfate -gel electrophoresis. Transferases a, p and E each appear as a single band on gel electrofocusing; transferases y and 6 are present as two and three bands, respectively, with each band catalytically active. Amino acid analysis indicated the five transferases to be either very closely related or identical in this respect.All enzyme species have a molecular weight of about 48 500 and consist of two apparently identical subunits. The spectrum of substrates is the same for each although the enzymes differ slightly in specific activity. As is the case for the rat liver enzymes, each of the human transferases binds bilirubin although this compound is not a substrate.

show abstract

Section: Specificitymentioning

confidence: 99%

Multiple Forms of Human Glutathione S‐Transferase and Their Affinity for Bilirubin

Kamisaka¹,

Habig²,

Ketley³

et al. 1975

European Journal of Biochemistry

Self Cite

275

112

View full text Add to dashboard Cite

show abstract

“…0-i-> OH unreactive towards GSH (it is a soft and weak electrophile) yet GSH conjugation is catalyzed quite effectively by GSH transferases (37)(38)(39). A comparison of the purified GSH transferases shows that BP4,5-oxide is a much better substrate for GSH transferases A and C than for B and E (Table 1 and Fig.…”

Section: Hncoch3mentioning

confidence: 99%

The Role of Glutathione in Detoxication

Ketterer¹,

Coles²,

Meyer³

1983

Environmental Health Perspectives

View full text Add to dashboard Cite

Glutathione (GSH) is a strong nucleophile which reacts well with soft electrophiles, but poorly with both weak and strong electrophiles. Weak electrophiles have low reactivity with all nucleophiles while strong electrophiles react well with weak nucleophiles including superabundant H20.There are enzymes, the GSH transferases, which catalyze GSH conjugation with all the types of electrophiles described above. In order to deal with the wide variety of potential substrates, a multiplicity of GSH transferases exists-each tissue having its own collection and each enzyme having a different substrate specificity. These enzymes are often very abundant, e.g., in the rat liver cytosol, their concentration is 0.2 mM.The following substrates are considered in some detail: 1-chloro-2,4-dinitrobenzene, the electrophile derived metabolically from paracetamol N-acetyliminoquinone?), benzo(a)pyrene-4-5-oxide, cholesterol-5a,6a-oxide, benzo(a)pyrene-7,8-diol-9,10-oxide and the electrophiles derived metabolically from aflatoxin B, (the 2,3-oxide?). According to the substrate, optimal enzyme rates vary over seven orders of magnitude from 10-1 to 10-12 mole/min/mg.Despite the wide embrace of the GSH transferases, not all metabolically produced electrophiles are substrates. We know of the following examples: N-methylol-4-aminoazobenzene and its 4'-hydroxy derivative (these are soft electrophiles and react well with GSH noncatalytically), N-sulfonyloxy-N-methyl-4-aminoazobenzene, N-sulfonyloxy-N-acetyl-2-aminofluorene (these are strong electrophiles which do not react selectively with GSH) and N-hydroxy-2-aminofluorene which appears to react only slowly with GSH. It is of interest in the present context that all these compounds are derived from either arylamine or arylamide carcinogens.Whether the reaction be enzymic or nonenzymic, conjugation with GSH is a very important means of detoxication accounting in some cases for up to 60% of the biliary metabolites. As seen in the example of aflatoxin B,, very low enzymic rates observed in vitro are sufficient to account for apparently high rates of biliary excretion of GSH conjugates.GSH transferases have evolved other functions apart from the catalysis of GSH conjugation. GSH transferase B participates in the hepatic uptake of bilirubin and the intracellular distribution of the heme prosthetic group. It also has GSH peroxidase activity which suggests that it might participate in the detoxication of by-products of oxygen utilization including those produced by the action of cytochrome P-450. It is shown that GSH transferase B inhibits lipid peroxidation in vitro. GlutathioneGlutathione (GSH), y-glutamylcysteinylglycine, is a molecule with the following important properties. Its cysteinyl residue provides a nucleophilic thiol important for the detoxication of electrophilic metabolites and metabolically produced oxidizing agents. Its net negative charge and overall hydrophilicity greatly increases the aqueous solubility of the lipophilic moieties with which it becomes conjugated. Its molecula...

show abstract

“…This concept was further promoted by both the experimental findings and theoretical considerations with model diol-epoxides and the diolepoxides of BzPy (19 The metabolism of BzPy is regulated by unique enzymes which include the various forms of cytochrome P-450 (23,24), epoxide hydratase (10, 11), glutathione S-transferase (12), the glucuronidation of benzo[a]pyrene metabolites (13). Understanding the enzymatic pathways may lead to a precise definition of factors regulating the formation of the ultimate carcinogenic form vis-a-vis the formation of detoxification forms.…”

Section: Fig 1 Hplc Analysis Of the Hydrolysis Products Derived Fromentioning

confidence: 99%

Enzymatic conversion of benzo(a)pyrene leading predominantly to the diol-epoxide r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene through a single enantiomer of r-7, t-8-dihydroxy-7,8-dihydrobenzo(a)pyrene.

Yang¹,

McCourt²,

Roller³

et al. 1976

Proc. Natl. Acad. Sci. U.S.A.

218

View full text Add to dashboard Cite

BiochemistryEnzymatic conversion of benzo [a]pyrene leading predominantly to the diol-epoxide r-7, t-8-dihydroxy-t-9, 10-oxy-7,8,9,10-tetrahydrobenzo[a] Baldeschwieler, May 10, 1976 ABSTRACT Benz alpyrene is metabolically and stereospecifically converted by mixed-function oxidases of rat liver microsomes and epoxide hydratase [glycol hydro-lyase (epoxide-forming), EC 4.2.1.631 to the single enantiomer (-)r-7,t-8-dihydroxy-7,8-dihydrobenzo[ajpyrene. This enantiomer is further metabolized stereoselectively by the mixed-function oxidases to predominantly the diol-epoxide, r-7,t-dihydroxy-t-

show abstract

K region benzo(α)pyrene-4,5-oxide is conjugated by homogeneous gluthathione S-transferases

Cited by 86 publications

References 10 publications

Multiple Forms of Human Glutathione S‐Transferase and Their Affinity for Bilirubin

Multiple Forms of Human Glutathione S‐Transferase and Their Affinity for Bilirubin

The Role of Glutathione in Detoxication

Enzymatic conversion of benzo(a)pyrene leading predominantly to the diol-epoxide r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene through a single enantiomer of r-7, t-8-dihydroxy-7,8-dihydrobenzo(a)pyrene.

Contact Info

Product

Resources

About