Prostaglandin H synthase oxidation of benzidine and o-dianisidine: reduction and conjugation of activated amines by thiols

Wise, Ronald W.; Zenser, Terry V.; Davis, Bernard B.

doi:10.1093/carcin/6.4.579

Cited by 29 publications

(14 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recently, a N-acetylcysteine conjugate has been isolated from a peroxidase-H202-benzidine-N-acetylcysteine reaction mixture and also identified as 3-(N-acetylcysteine-S-yl)-benzidine (106). An analogous GSH conjugate has also been isolated from a prostaglandin H synthase-arachnidonate-benzidine-GSH reaction mixture (107). The DNA adducts isolated from the dog bladder after the in vivo 14C-benzidine administration was 10% N-(deoxyguanosin-8-yl)[N'-acetylbenzidine but the rest was unidentified.…”

Section: N-oxidationmentioning

confidence: 99%

Free-radical-mediated DNA binding.

O’Brien¹

1985

Environ Health Perspect

View full text Add to dashboard Cite

Free-radical metabolites can be generated metabolically by a one-electron reductase-catalyzed reaction or a "peroxidase" catalyzed oxidation or by photoactivation of a wide variety of aromatic xenobiotics. Radicals may also be generated during lipid peroxidation. Some radicals can react with DNA or bind covalently or noncovalently as a dismutation product or as a dimer, trimer or polymeric product. Modification to the DNA can result in single-strand breaks, loss of template activity, and crosslinking. The binding can prevent enzymic digestion. In some cases, the radicals react with oxygen, resulting before conversion to DNA reactive oxygen species. Most radicals probably do not interact with DNA.

show abstract

Section: N-oxidationmentioning

confidence: 99%

Free-radical-mediated DNA binding.

O’Brien¹

1985

Environ Health Perspect

View full text Add to dashboard Cite

show abstract

“…The peroxygenation mechanism for metabolism of ABZ is dramatically different from the electron transfer mechanism observed for PHS metabolism of benzidine, the diamine analogue of ABZ (12)(13)(14)(41)(42)(43)(44). Both chemical and enzymatic experiments indicate the oxidation of benzidine to one-electron (cation radical) and two-electron (benzidinediimine) oxidized products.…”

Section: H]abz To [mentioning

confidence: 92%

Peroxygenase Metabolism of N-Acetylbenzidine by Prostaglandin H Synthase

Zenser

Lakshmi

Hsu

et al. 1999

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Synthesis of prostaglandin H 2 by prostaglandin H synthase (PHS) results in a two Prostaglandin H synthase (PHS)1 catalyzes the metabolism of arachidonic acid in the presence of molecular oxygen to form prostaglandin (PG) H 2 (1). PGH 2 is the common substrate utilized to synthesize a family of biologically important compounds referred to as prostanoids. There are two PHS isozymes, COX-1 and COX-2, which are encoded by two different genes (2, 3). COX-1 is the constitutive enzyme, whereas COX-2 is inducible. Whereas these isozymes differ substantially with respect to their expression and biology, they have a similar structure and express the same two catalytic activities (for a review, see Ref. 4). Both isozymes catalyze a cyclooxygenase (bis-oxygenase) reaction in which arachidonic acid is converted to PGG 2 and a peroxidase reaction in which PGG 2 undergoes a two-electron reduction to PGH 2 . The two-electron oxidation of PHS yields the peroxidase spectral intermediate I that must be reduced to regenerate the resting enzyme (5). A reducing cofactor(s) accomplishes this task and is required for the peroxidase reaction. By donating electrons to the oxidized PHS intermediate, reducing cofactors undergo co-oxidation. The peroxidase activity of both PHS isozymes is essential for biological activity. The biological reducing cofactor(s) for the peroxidatic activity of PHS is unknown. Many naturally occurring compounds have been tested for their efficiency in functioning as reducing cofactors (6). These compounds include NADPH, NADH, glutathione, methionine, tryptophan, epinephrine, ascorbic acid, lipoic acid, and uric acid. Whereas the last four compounds were efficient cofactors, uric acid was considered the most likely endogenous candidate. A large number of synthetic chemicals were also found to exhibit significant reducing cofactor activity.During reduction of the 15-hydroperoxy group of PGG 2 to a hydroxy group (PGH 2 ), prostaglandin hydroperoxidase oxidizes, reducing cofactors by electron or oxygen transfer (for a review, see Ref. 7). Most reducing cofactors donate an electron. Nitrogen-, carbon-, and sulfur-centered free radicals have been detected. For some cofactors, the radical product can undergo a second one-electron oxidation to form a two-electron oxidation product. In addition, the initial free radical product may disproportionate to give a two-electron oxidation product, i.e. an iminium cation, and the original substrate (8). Other radical products may couple, forming dimers or trimers. With sulfide cofactors, the hydroperoxidase catalyzes peroxide reduction by the direct transfer of the peroxide oxygen to the acceptor molecule (9, 10). Except for sulfide reducing cofactors, no other peroxygenase reaction has been reported for PHS.Aromatic and heterocyclic amines represent an important

show abstract

“…Wise et al (30) and Josephy and Iwaniw (31) have reported the formation of benzidineglutathione or benzidine-N-acetylcysteine conjugates during the peroxidase-catalyzed oxidation of benzidine to free radical intermediates in the presence of glutathione or N-acetylcysteine, respectively. Wise et al (30) and Josephy and Iwaniw (31) have reported the formation of benzidineglutathione or benzidine-N-acetylcysteine conjugates during the peroxidase-catalyzed oxidation of benzidine to free radical intermediates in the presence of glutathione or N-acetylcysteine, respectively.…”

Section: Dlscusslonmentioning

confidence: 99%

The oxidation of 4-aminobiphenyl by horseradish peroxidase

Hughes¹,

Smith²,

Eling³

1992

Chem. Res. Toxicol.

View full text Add to dashboard Cite

The oxidation of the carcinogen 4-aminobiphenyl (4-ABP) catalyzed by the model peroxidase enzyme horseradish peroxidase (HRP) was investigated. 4-ABP served as a reducing cosubstrate for HRP during the enzyme-catalyzed reduction of the synthetic hydroperoxide, 5-phenyl-4-penten-1-yl hydroperoxide, to its corresponding alcohol. Spectral analysis during the incubation of HRP, 4-ABP, and H2O2 showed an increase in absorbance at 230 and 325 nm and decrease at 270 nm, suggesting metabolite formation. Oxygen consumption was not detected in incubations of HRP, 4-ABP, and H2O2. However, oxygen uptake was observed after the addition of glutathione, which indicated that a free radical metabolite of 4-ABP was formed by the peroxidase. The 4-ABP free radical reacted with glutathione forming a glutathionyl radical which, in turn, reacted with and consumed oxygen. HPLC analysis of organic extracts of incubations with HRP, [3H]-4-ABP, and H2O2 showed the formation of one major peak identified by mass spectroscopy as 4,4'-azobis(biphenyl). The addition of glutathione to the incubations decreased the formation of 4-ABP metabolites, suggesting a reduction of the 4-ABP free radical and/or the formation of glutathione conjugates. Subsequent HPLC analysis of incubations including [35S]glutathione indicated formation of several unidentified 4-ABP-glutathione conjugates as well as recovery of parent compound. These studies suggest that HRP metabolizes 4-ABP by a one-electron oxidation mechanism, resulting in formation of a free radical. This radical can either react with a second radical to form azobis(biphenyl), be reduced by glutathione back to parent, or react with glutathione to form glutathione conjugates.

show abstract

Prostaglandin H synthase oxidation of benzidine and o-dianisidine: reduction and conjugation of activated amines by thiols

Cited by 29 publications

References 0 publications

Free-radical-mediated DNA binding.

Free-radical-mediated DNA binding.

Peroxygenase Metabolism of N-Acetylbenzidine by Prostaglandin H Synthase

The oxidation of 4-aminobiphenyl by horseradish peroxidase

Contact Info

Product

Resources

About