Identification of nevadensin as an important herb-based constituent inhibiting estragole bioactivation and physiology-based biokinetic modeling of its possible in vivo effect.
Estragole is a natural constituent of several herbs and spices including sweet basil. In rodent bioassays, estragole induces hepatomas, an effect ascribed to estragole bioactivation to 1'-sulfooxyestragole resulting in DNA adduct formation. The present paper identifies nevadensin as a basil constituent able to inhibit DNA adduct formation in rat hepatocytes exposed to the proximate carcinogen 1'-hydroxyestragole and nevadensin. This inhibition occurs at the level of sulfotransferase (SULT)-mediated bioactivation of 1'-hydroxyestragole. The Ki for SULT inhibition by nevadensin was 4 nM in male rat and human liver fractions. Furthermore, nevadensin up to 20 microM did not inhibit 1'-hydroxyestragole detoxification by glucuronidation and oxidation. The inhibition of SULT by nevadensin was incorporated into the recently developed physiologically based biokinetic (PBBK) rat and human models for estragole bioactivation and detoxification. The results predict that co-administration of estragole at a level inducing hepatic tumors in vivo (50mg/kg bw) with nevadensin at a molar ratio of 0.06, representing the ratio of their occurrence in basil, results in almost 100% inhibition of the ultimate carcinogen 1'-sulfooxyestragole when assuming 100% uptake of nevadensin. Assuming 1% uptake, inhibition would still amount to more than 83%. Altogether these data point at a nevadensin-mediated inhibition of the formation of the ultimate carcinogenic metabolite of estragole, without reducing the capacity to detoxify 1'-hydroxyestragole via glucuronidation or oxidation. These data also point at a potential reduction of the cancer risk when estragole exposure occurs within a food matrix containing SULT inhibitors compared to what is observed upon exposure to pure estragole.
Alhusainy
W
W
Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands. wasma.alhusainy@wur.nl
Paini
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Punt
A
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Louisse
J
J
Spenkelink
A
A
Vervoort
J
J
Delatour
T
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Scholz
G
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Schilter
B
B
Adams
T
T
van Bladeren
P J
PJ
Rietjens
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D000081248:Allylbenzene Derivatives; D000818:Animals; D000840:Anisoles / Q000378:metabolism / Q000493:pharmacokinetics*; D002273:Carcinogens / Q000493:pharmacokinetics*; D018736:DNA Adducts / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000494:pharmacology*; D020719:Glucuronides / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D018649:Ocimum basilicum; D010084:Oxidation-Reduction; D010936:Plant Extracts; D051381:Rats; D017207:Rats, Sprague-Dawley; D015238:Sulfotransferases / Q000037:antagonists & inhibitors*; D023382:Toxicity Tests, Acute
D000081248:Allylbenzene Derivatives; D000840:Anisoles; D002273:Carcinogens; D018736:DNA Adducts; D047309:Flavones; D020719:Glucuronides; D010936:Plant Extracts; C023982:nevadensin; C014037:1'-hydroxyestragole; C035921:1'-acetoxyestragole; C007633:estragole; D015238:Sulfotransferases