title: Oral administration of naturally occurring coumarins leads to altered phase I and II enzyme activities and reduced DNA adduct formation by polycyclic aromatic hydrocarbons in various tissues of SENCAR mice.
abstract: Several naturally occurring coumarins, to which humans are routinely exposed in the diet, were previously found to inhibit P450-mediated metabolism of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) in vitro, block DNA adduct formation in mouse epidermis and inhibit skin tumor initiation by B[a]P and/or DMBA when applied topically to mice. The present study was designed to investigate the effects of two of these compounds, of the linear furanocoumarin type, when given orally (70 mg/kg per os, four successive daily doses), on P450 and glutathione S-transferase (GST) activities and DNA adduct formation by B[a]P and DMBA in various mouse tissues. Imperatorin and isopimpinellin significantly blocked ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O:-dealkylase (PROD) activities in epidermis at 1 and 24 h after oral dosing. Imperatorin and isopimpinellin modestly inhibited EROD activities in lung and forestomach at 1 h and significantly inhibited PROD activities in lung and forestomach at 1 h after the final oral dose. Twenty-four hours after the final oral dose of imperatorin or isopimpinellin EROD and PROD activities remained inhibited in epidermis and lung. However, forestomach P450 activity had returned to control levels. Interestingly, imperatorin and isopimpinellin treatment inhibited liver EROD activity at 1 h, had no effect on PROD activity at this time point, but elevated both these enzyme activities at 24 h. Elevated EROD and PROD activities coincided with elevated hepatic P450 content. Imperatorin and isopimpinellin treatment also increased liver cytosolic GST activity at both 1 and 24 h after the final oral dose by 1.6-fold compared with corn oil controls. Oral administration of imperatorin and isopimpinellin also had a protective effect against DNA adduct formation by B[a]P and DMBA. Imperatorin pretreatment decreased formation of DNA adducts by DMBA in forestomach. Pretreatment with isopimpinellin led to reduced DNA adduct levels in liver (B[a]P), lung (B[a]P) and mammary epithelial cells (DMBA). These results suggest that imperatorin and isopimpinellin may have potential chemopreventive effects when administered in the diet.
authors.affiliation: University of Texas MD Anderson Cancer Center, Science Park-Research Division, Department of Carcinogenesis, PO Box 389, Smithville, TX 78957, USA.
authors.forename: H E
authors.initials: HE
authors.lastname: Kleiner
authors.forename: S V
authors.initials: SV
authors.lastname: Vulimiri
authors.forename: L
authors.initials: L
authors.lastname: Miller
authors.forename: W H
authors.initials: WH
authors.lastname: Johnson
authors.forename: C P
authors.initials: CP
authors.lastname: Whitman
authors.forename: J
authors.initials: J
authors.lastname: DiGiovanni
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism* / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018736:DNA Adducts / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D011564:Furocoumarins / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D018632:Mice, Inbred SENCAR; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D013270:Stomach / Q000187:drug effects / Q000201:enzymology
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D018736:DNA Adducts; D011564:Furocoumarins; C056612:benzo(a)pyrene-DNA adduct; C015304:isopimpinellin; D001564:Benzo(a)pyrene; D015127:9,10-Dimethyl-1,2-benzanthracene; D003577:Cytochrome P-450 Enzyme System; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D005982:Glutathione Transferase; C031534:imperatorin