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.

Antigenotoxic activity of naturally occurring furanocoumarins

“…Kleiner et al [2001] demonstrated that the CYP inducing effects of furanocoumarins, imperatorin and isopimpinellin were apparently found in the liver, because the CYP activities in skin epidermis, forestomach, and lung remained unchanged or suppressed at 24 hr after the last of 4 consecutive oral doses in mice. In addition, the DNA adduct formation by B[a61533P and/or DMBA was also reduced by NOFs in these tissues [Kleiner et al, 2001]. Perhaps the hepatic CYPs, GSTs, and NAD(P)H quinone oxidoreductase coupled with sustained suppression of CYPs in the extrahepatic tissues allowed these carcinogens to be metabolized and cleared in the liver.…”

“…For example, another chemopreventive agent oltipraz is thought to suppress hepatocarcinogenesis due to aflatoxin B 1 through the induction of glutathione S-transferases (GSTs), but it is also found to modulate hepatic CYP by acting both as a reversible inhibitor and an inducer of CYP1A and CYP2B [Langouet et al, 1997]. Kleiner et al [2001] demonstrated that the CYP inducing effects of furanocoumarins, imperatorin and isopimpinellin were apparently found in the liver, because the CYP activities in skin epidermis, forestomach, and lung remained unchanged or suppressed at 24 hr after the last of 4 consecutive oral doses in mice. In addition, the DNA adduct formation by B[a61533P and/or DMBA was also reduced by NOFs in these tissues [Kleiner et al, 2001].…”

Anticancer Effects of Imperatorin Isolated from Angelica dahurica: Induction of Apoptosis in HepG2 Cells through both Death-Receptor- and Mitochondria-Mediated Pathways

“…However, when cisplatin was used as a second-line therapy with doses varying from 60 to 175 mg/m 2 /cycle, the RR ranged from 0 to 40% (table 1) [6,7,8,9,10,11]. …”

Inhibition of estrogen-induced mammary tumor formation in MMTV-aromatase transgenic mice by 4-chlorophenylacetate

“…4-CPA treatment of the mice had no significant effect on either basal or DMBA-induced EROD activity. Measurement of EROD activity in the presence of mammary microsomal protein was more difficult due to the lower yield of microsomes and CYP1 levels [23]. Therefore, we pooled mammary derived microsomes obtained from 5 mice in each treatment group in order to obtain enough protein for detecting EROD activity.…”