Formation of N-(glutathion-S-methylene)-4-aminoazobenzene following metabolic oxidation of the N-methyl group of the carcinogen, N-methyl-4-aminoazobenzene

Ketterer, Brian; Srai, Sks; Waynforth, B.; Tullis, D.L.; Evans, Frederick E.; Kadlubar, Fred F.

doi:10.1016/0009-2797(82)90059-x

Cited by 33 publications

(5 citation statements)

References 20 publications

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“…The N-methyl oxidation of MAB or 4'-OH-MAB gives an intermediate which is a soft electrophile reacting readily with GSH and believed to be an Nmethylol or a methimine (49). GSH conjugation of the intermediate derived from MAB gives N4gluta-thion-S-methylene)4-aminoazobenzene (GSCH2AB) (49) or, in the case of 4'-OH-MAB, 4'-OH-GSCH2AB which is sulfated in vivo to 4'-sulfonyloxy-GSCH2AB (50) (Fig.…”

Section: Benzo(a)pyrene45-oxide (Bp45-oxide)mentioning

confidence: 99%

“…GSH conjugation of the intermediate derived from MAB gives N4gluta-thion-S-methylene)4-aminoazobenzene (GSCH2AB) (49) or, in the case of 4'-OH-MAB, 4'-OH-GSCH2AB which is sulfated in vivo to 4'-sulfonyloxy-GSCH2AB (50) (Fig. 5).…”

Section: Benzo(a)pyrene45-oxide (Bp45-oxide)mentioning

confidence: 99%

“…5). In in vitro experiments involving the microsomal oxidation of MAB in the presence of GSH, the yield of GSCH2AB is directly proportional to the GSH concentration in the incubation (49), which is characteristic of a nonenzymic reaction. The reaction is not dependent on the microsomal GSH transferases which are present in the incubation nor is it affected by added soluble GSH transferases.…”

Section: Benzo(a)pyrene45-oxide (Bp45-oxide)mentioning

confidence: 99%

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The Role of Glutathione in Detoxication

Ketterer¹,

Coles²,

Meyer³

1983

Environmental Health Perspectives

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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...

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Section: Benzo(a)pyrene45-oxide (Bp45-oxide)mentioning

confidence: 99%

Section: Benzo(a)pyrene45-oxide (Bp45-oxide)mentioning

confidence: 99%

Section: Benzo(a)pyrene45-oxide (Bp45-oxide)mentioning

confidence: 99%

See 1 more Smart Citation

The Role of Glutathione in Detoxication

Ketterer¹,

Coles²,

Meyer³

1983

Environmental Health Perspectives

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“…N-Acetyl-S-{ N-[4,6-bis(dimethylamino)-1,3,5-triazin-2-y& N-methylaminomethyl} cysteine (7).-A mixture of aqueous formaldehyde (37% w/v; 3 ml, 37 mmol), methanol (20 ml), Nacetyl-L-cysteine (1 .O g, 6.1 mmol) and 2,4-bis(dimethylamino)-6-methylamino-1,3,5-triazine ' (980 mg, 5 mmol) was stirred at 37 "C for 2 h before being cooled to 0 "C for 1 h. The precipitate was filtered off and washed with a small volume of cold methanol to give the cysteine deriuatiue (7) as a white powder (1.30 g; 70% based on the pentamethyl melamine) which decomposed without melting at <60°C (Found C, 45.55; H, 6.9; N, 26.1. C14H25N703S requires C, 45.25; H, 6.8; N, 26.4%); v, , , .…”

Section: N-acetyl-s-(n'-phenylureidornethyi)cysteine (15b)--n'-mentioning

confidence: 99%

The formation and metabolism of N-hydroxymethyl compounds. Part 6. The synthesis of S-amidomethyl-, S-ureidomethyl-, and S-(1,3,5-triazin-2-ylaminomethyl)-glutathione derivatives

ADDISON¹,

Cunningham²,

Gate³

et al. 1985

J. Chem. Soc., Perkin Trans. 1

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“…The N-methyl oxidation of MAB or 4'-OH-MAB gives an intermediate which is a soft electrophile reacting readily with GSH and believed to be an Nmethylol or a methimine (49). GSH conjugation of the intermediate derived from MAB gives N4glutathion-S-methylene)4-aminoazobenzene (GSCH2AB) (49) or, in the case of 4'-OH-MAB, 4'-OH-GSCH2AB which is sulfated in vivo to 4'-sulfonyloxy-GSCH2AB (50) (Fig. 5).…”

Section: Aflatoxin B1-23-oxide (Afb1-oxide)mentioning

confidence: 99%

The role of glutathione in detoxication

Ketterer¹,

Coles²,

Meyer³

1983

Environ Health Perspect

346

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 H2O. 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-5α,6α-oxide, benzo(a)pyrene-7,8-diol-9,10-oxide and the electrophiles derived metabolically from aflatoxin B1 (the 2,3-oxide?). According to the substrate, optimal enzyme rates vary over seven orders of magnitude from 10−5 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 B1, 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.

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Formation of N-(glutathion-S-methylene)-4-aminoazobenzene following metabolic oxidation of the N-methyl group of the carcinogen, N-methyl-4-aminoazobenzene

Cited by 33 publications

References 20 publications

The Role of Glutathione in Detoxication

The Role of Glutathione in Detoxication

The formation and metabolism of N-hydroxymethyl compounds. Part 6. The synthesis of S-amidomethyl-, S-ureidomethyl-, and S-(1,3,5-triazin-2-ylaminomethyl)-glutathione derivatives

The role of glutathione in detoxication

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