Arene oxides and the NIH shift: The metabolism, toxicity and carcinogenicity of aromatic compounds

Daly, John W.; Jerina, Donald M.; Witkop, Bernhard

doi:10.1007/bf01946135

Cited by 622 publications

(235 citation statements)

References 146 publications

Supporting

Mentioning

220

Contrasting

Unclassified

Order By: Relevance

“…Some information on the order in which the substituents are introduced into the aromatic ring of tomaymycin was obtained by feeding DL- [5-3H] [7a-14C] tryptophan to the producing organism and determining the tritium retention in the antibiotic 21). The low tritium retention in tomaymycin (17%) by consideration of NIH shift rules 22) was indicative that the most likely pathway involved insertion of the 8 hydroxy substituent prior to the 7 hydroxy group. When the same species of tryptophan was fed to the sibiromycin-producing culture an 85% retention of tritium was found in the antibiotic indicative of an NIH shift.…”

mentioning

confidence: 99%

Pyrrolo(1,4)benzodiazepine antitumor antibiotics. Comparative aspects of anthramycin, tomaymycin and sibiromycin.

Hurley

1977

J. Antibiot.

171

View full text Add to dashboard Cite

mentioning

confidence: 99%

Pyrrolo(1,4)benzodiazepine antitumor antibiotics. Comparative aspects of anthramycin, tomaymycin and sibiromycin.

Hurley

1977

J. Antibiot.

171

View full text Add to dashboard Cite

“…The initial stage in the mammalian metabolism of PAH involves the cyctochrome P-450 monooxygenase system, which catalyzes the oxidative metabolism of these lipophilic compounds, to form arene oxides (Daly et al, 1972). Arene oxides are relatively unstable and undergo at least five reactions, including: i) non-enzymatic rearrangement to phenols, ii) enzymatic hydration by epoxide hydrolase, to yield frans-dihydrodiols, iii) conjugation with glutathione (GSH), either enzymatically by glutathione 5-epoxide transferase or nonenzymatically, iv) reduction of the arene oxide back to the parent hydrocarbon and v) binding to nucleophilic sites in proteins and nucleic acids ( fig.…”

Section: Biochemical Role Of Epoxidation Reactionsmentioning

confidence: 99%

Biocatalysts for production of chiral epoxides

Mahmoudian

Michael

1992

Appl Microbiol Biotechnol

View full text Add to dashboard Cite

An extensive screen for microorganisms capable of growth on olefins was carried out. Over 100 bacterial strains (mesophilic, thermophilic) were isolated in pure culture with gaseous or liquid (internal & terminal) olefins as the sole source of carbon and energy. The organisms included Aero coccus, Aeromonas,Alcaligenes, Flavobacterium, Micrococcus, Moraxella, Nocardia, Pseudomonas, Staphylococcus, Streptomyces and Vibrio spp. and a variety of Gram-negative, Gram-positive and Gram-variable rods/coccobacilli not yet identified. Given the success of isolating many different genera of alkene-utilizing bacteria, it would suggest that the ability to utilize olefin hydrocarbons is more widespread in nature than previously recognized.Initial studies involved testing a collection of strains for i) growth rate on the substrate of isolation and ii) evidence of epoxide accumulation from lower gaseous olefins. All of the 18 ethene-and propene-utilizing bacteria tested, stereospecifically formed R-1,2-epoxypropane (ee=90-96%), R -l,2-epoxybutane (ee=90-98%) and trans-(2/?,37?)-epoxybutane (ee=64-88%), as analyzed by chiral complexation glc. A particularly promising strain of Micrococcus sp. M90C was selected to demonstrate: a) Induction of epoxidation activity in carbohydrate-grown cells. b) Optimization of a biotransformation process for production of epoxyethane. c) Involvement of a specific monooxygenase in the formation of chiral epoxides. d) Stereoselectivity of epoxyalkane degradation. e) Substrate specificity toward a range of olefins.Micrococcus sp. M90C stereospecifically formed S-(+)-phenyl glycidyl ether (ee=93%) and /?-(+)-phenyl methyl sulphoxide (ee>98%), as analyzed by chiral-shift NMR and HPLC. The ability to catalyze heteroatom oxygenation as well as epoxidation of a wide range of olefins in high optical and chemical yields, demonstrates its potential as a 'general-purpose' biocatalyst for the production of optically pure oxygenated compounds.Two other promising ethene-utilizing bacteria (M26, M93 A) each catalyzed the stereospecific formation of S-(+)-phenyl glycidyl ether (ee=93%). This has attracted considerable industrial interest and is currently under investigation at ICI for commercial production of optically active./1-blockers. In addition to Micrococcus sp. M90C, the substrate specificities of 6 other organisms were studied in order to probe the active site of the enzymes involved. The pattern of reactivity for the group of 4 ethene-(M26, M90C, M93A, M186) and 2 propene-(M142, M l 56) utilizers differed from that expected with peracids, suggesting a considerable degree of enzymatic control.The nature of the substrate, however, modulated enzymatic epoxidations in Staphylcoccus sp. M97B. CONTENTS

show abstract

Section: Introductionmentioning

confidence: 99%

“…3.3.2.3) (Daly, Jerina & Witkop, 1972;Oesch, 1973;Jerina & Daly, 1974). Epoxides may undergo conjugation with glutathione (Jerina et al, 1970;Nemoto et al, 1975) or form phenols non-enzymatically (Daly et al, 1972). Alternatively, epoxides may bind with subcellular macromolecules resulting in cytotoxicity, mutagenicity and carcinogenicity (Daly et al, 1972;Oesch, 1973;Jerina et al, 1974;Wiebel, Whitlock & Gelboin, 1974).…”

Section: Introductionmentioning

confidence: 99%

“…Epoxides may undergo conjugation with glutathione (Jerina et al, 1970;Nemoto et al, 1975) or form phenols non-enzymatically (Daly et al, 1972). Alternatively, epoxides may bind with subcellular macromolecules resulting in cytotoxicity, mutagenicity and carcinogenicity (Daly et al, 1972;Oesch, 1973;Jerina et al, 1974;Wiebel, Whitlock & Gelboin, 1974). While EH inactivates epoxides, it also participates in the formation of carcinogenic dihydrodiol epoxides such as 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene 9,10-oxide (Malaveille et al, 1975).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Epoxide hydrolase activity in human skin.

O’Neill¹,

Rawlins²,

Chapman³

1981

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 Epoxide hydrolase (EH) activity was measured in biopsied skin (n = 42) using 7-[H3]-styrene oxide as substrate, and separation of the products by high performance liquid chromatography. 2 EH activity (mean + s.d.) was present in separated epidermis (139 + 105 pmol glycol formed mg-' min-1) and dermis (165 + 120 pmol glycol formed mg-' microsomal protein min-1). 3 Whole skin EH activity (mean s.d.) varied widely (433 254 pmol glycol formed mg-microsomal protein min-1). 4 No significant difference in EH activity was observed in skin from breast, penis and leg. 5 Skin EH activity does not appear to contribute significantly to the systemic metabolism of epoxide, but may be important in determining the effects of epoxides formed within the epidermis.

show abstract

Arene oxides and the NIH shift: The metabolism, toxicity and carcinogenicity of aromatic compounds

Cited by 622 publications

References 146 publications

Pyrrolo(1,4)benzodiazepine antitumor antibiotics. Comparative aspects of anthramycin, tomaymycin and sibiromycin.

Pyrrolo(1,4)benzodiazepine antitumor antibiotics. Comparative aspects of anthramycin, tomaymycin and sibiromycin.

Biocatalysts for production of chiral epoxides

Epoxide hydrolase activity in human skin.

Contact Info

Product

Resources

About