ABSTRACT
The purpose of the present study was to examine whether or not (-)-Menthol affects the distribution and metabolism of 2-aminofluorene (AF) in Sprague-Dawley rats. The AF, acetylated AF and AF metabolites were determined by using high performance liquid chromatography. AF was administered orally alone, with (-)-Menthol at the same time, and after 24-hour (-)-Menthol pretreatment and then urine, stool, blood and tissues from liver, kidneys, stomach, colon and bladder were collected and assayed for AF and its metabolites. Compared to the control group, (-)-Menthol caused an increase of the metabolites excreted in the urine and stool. The major metabolite excreted both in the urine and in the stool was 9-OH-AAF. The liver was the major metabolism center and the major residual metabolite of AF in the liver was 9-OH-AAF. When AF was given for 24 hours with (-)-Menthol to SD rats, the rate of carcinogen acetylation is decreased in bladder, blood, colon, kidney and liver tissues.
Subject(s)
Carcinogens/pharmacokinetics , Fluorenes/pharmacokinetics , Menthol/pharmacology , Administration, Oral , Animals , Carcinogens/administration & dosage , Carcinogens/analysis , Chromatography, High Pressure Liquid , Drug Interactions , Fluorenes/administration & dosage , Fluorenes/analysis , Liver/drug effects , Liver/metabolism , Male , Menthol/administration & dosage , Rats , Rats, Sprague-Dawley , Stereoisomerism , Tissue Distribution/drug effectsABSTRACT
BACKGROUND: The effects of paclitaxel on the in vivo distribution and the levels of N-acetylation of 2-aminofluorene (AF) and AF-DNA adducts in Sprague-Dawley (SD) rats were studied. METHODS AND RESULTS: For in vivo examination, pretreatment with paclitaxel (50 mg/kg) 48 hours prior to the administration of AF (50 mg/kg) resulted in a 28% and 43% decrease, respectively, in the urinary and fecal recovery of N-acetyl-2-aminofluorene (AAF), and a 22% decrease in the metabolic clearance of AF to AAF. Paclitaxel did not affect the Michaelis-Menten parameters for N-acetyltransferase (NAT) activity in blood, liver, lung, colon and bladder. Similarly, the Km value for AF in the examined tissues was not affected by paclitaxel. However, the Vmax value estimate of liver NAT activity was significantly decreased after paclitaxel pretreatment. Following exposure of rats to AF with and without pretreatment with paclitaxel, DNA-AF adducts were examined in the target tissues, liver, colon and bladder, and also in non-target tissues, lung and circulating leukocytes. The DNA-AF adducts in the liver, bladder, lung, colon and leukocytes were decreased by pretreatment with paclitaxel. CONCLUSION: This is the first finding to show that paclitaxel affects AF distribution and N-acetylation and DNA adduct in SD rats in vivo.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Arylamine N-Acetyltransferase/metabolism , DNA Adducts/drug effects , Fluorenes/pharmacology , Paclitaxel/pharmacology , Acetylation/drug effects , Animals , Drug Antagonism , Fluorenes/pharmacokinetics , Liver/drug effects , Liver/enzymology , Male , Rats , Rats, Sprague-DawleyABSTRACT
N-Acetyltransferases (NATs) plays an important role in the first step of arylamine compounds metabolism. Polymorphic NAT is coded for rapid or slow acetylatoion phenotypes, which are recognized to affect cancer risk related to environmental exposure. Aloe-emodin has been shown to exit anticancer activity. The purpose of this study is to examine whether or not aloe-emodin could affect arylamine N-acetyltransferase (NAT) activity and gene expression (NAT mRNA) and DNA-2-aminofluorene (DNA-AF) adduct formation in mouse leukemia cells (L 1210). By using high performance liquid chromatography, N-acetylation and non-N-acetylation of AF were determined and quantitated. By using reverse transcriptase-polymerase chain reaction (RT-PCR) and PCR, NAT mRNA was determined and quantitated. Aloe-emodin displayed a dose-dependent inhibition to cytosolic NAT activity and intact mice leukemia cells. Time-course experiments indicated that N-acetylation of AF measured from intact mice leukemia cells were inhibited by aloe-emodin for up to 24h. Using standard steady-state kinetic analysis, it was demonstrated that aloe-emodin was a possible uncompetitive inhibitor to NAT activity in cytosols. The DNA-AF adduct formation in mouse leukemia cells were inhibited by aloe-emodin. The NAT1 mRNA in mouse leukemia cells were also inhibited by aloe-emodin. This report is the first demonstration which showed aloe-emodin affect mice leukemia cells NAT activity, gene expression (NAT1 mRNA) and DNA-AF on adduct formation.
