Reactive Metabolites as Key Intermediates in Pharmacologic and Toxicologic Responses: Examples from Chemical Carcinogenesis

Miller, Elizabeth C.; Miller, James A.

doi:10.1007/978-1-4757-0674-1_1

Cited by 7 publications

(6 citation statements)

References 20 publications

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“…Therefore, in the present study, an incubation of urine with the latter enzyme was inevitable to measure the complete excretion of OHE. Because the pH optimum of β-glucuronidase is slightly acidic (pH 5) and OHE has been shown to isomerize to p-methoxycinnamyl alcohol (7) with increasing acidity (21), the stability of OHE at pH 5 and pH 2 was tested. Figure 3 shows a rapid degradation of OHE at pH 5 and at the enzyme's temperature optimum at 37 °C, while its stability at room temperature was still satisfactory.…”

Section: Resultsmentioning

confidence: 99%

“…To date, indications for its formation come from scavenging reactions indicating the formation of the sulfate and from the decrease in incidence of hepatocellular carcinoma by application of the sulfotransferase inhibitor pentachlorphenol to rats . Further evidence for adverse effects comes from the detection of adducts of OHE with the DNA by HPLC analysis , . To date, the metabolites p -allylphenol and OHE have only been detected as glucuronic acid conjugates, and the intermediate sulfate ester of OHE has been postulated.…”

Section: Introductionmentioning

confidence: 99%

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Study of the Metabolism of Estragole in Humans Consuming Fennel Tea

Zeller

Horst

Rychlik

2009

Chem. Res. Toxicol.

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The metabolism of the potent carcinogen estragole was investigated in humans after consumption of fennel tea by analyses of its metabolites in blood plasma and urine. Stable isotope dilution assays based on LC-MS/MS detection revealed that 1'-hydroxylation of estragole happened very fast as the concentration of conjugated 1'-hydroxyestragole in urine peaked after 1.5 h, whereas it was no longer detectable after 10 h. Besides the formation of less than 0.41% conjugated 1'-hydroxyestragole of the estragole dose administered, the further metabolite p-allylphenol was generated from estragole in a higher percentage (17%). Both metabolites were also detected in blood plasma in less than 0.75-2.5 h after consumption of fennel tea. In contrast to this, no estragole was present in these samples above its detection limit. From the results, it can be concluded that an excess of the major fennel odorant trans-anethole principally does not interfere with estragole metabolism, whereas influences on the quantitative composition of metabolites cannot be excluded. The presence of a sulfuric acid conjugate of estragole could not be confirmed, possibly due to its high reactivity and lability.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Study of the Metabolism of Estragole in Humans Consuming Fennel Tea

Zeller

Horst

Rychlik

2009

Chem. Res. Toxicol.

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“…It is known that for some compounds, including polycyclic aromatic hydrocarbon, nitroso-, and aminoazo-containing chemicals, to become mutagenic or carcinogenic, they first require metabolic activation by P450 enzymes to chemically reactive species [88]. Reactive intermediates that are hard electrophiles react irreversibly with hard nucleophiles such as amino-groups of DNA bases [47].…”

Section: Dna Basesmentioning

confidence: 99%

Detecting reactive drug metabolites for reducing the potential for drug toxicity

Grillo¹

2015

Expert Opinion on Drug Metabolism & Toxicology

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“…Miller and Miller (1982 ) argued that the covalent binding of reactive metabolites of chemicals to DNA could direct mutagenic events and Lutz (1979) suggested that the relative carcinogenicity of various chemicals could be compared by determining their "covalent binding index", that is, a ratio of chemical bound per mg DNA to the administered dose of the chemical. Some examples of the covalent binding index in liver among well-known carcinogens include acetylaminofluorene, 260; dimethylnitrosamine, 5900; aflatoxin Critical Reviews in Toxicology Downloaded from informahealthcare.com by University of California San Francisco on 11/18/14…”

Section: B Binding To Dnamentioning

confidence: 99%