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P N Magee

Publications and source records attributed to P N Magee.

At least 19 recordsLinked to original sources
PubMed1992

Reduced blood clearance and increased urinary excretion of N-nitrosodimethylamine in patas monkeys exposed to ethanol or isopropyl alcohol.

Low concentrations of N-nitrosodimethylamine are metabolized in rodent and human liver by cytochrome P450IIE1, an activity competitively inhibitable by ethanol. In rodents coadministration of ethanol with N-nitrosodimethylamine results in increased tumorigenicity in extrahepatic organs, probably as a result of reduced hepatic clearance. To test this concept in a primate, the effects of ethanol cotreatment on the pharmacokinetics of N-nitrosodimethylamine were measured in male patas monkeys. Ethanol, 1.2 g/kg given p.o. before i.v. N-nitrosodimethylamine (1 mg/kg) or concurrently with an intragastric dose resulted in a 10-50-fold increase in the area under the blood concentration versus time curves and a 4-13-fold increase in mean residence times for N-nitrosodimethylamine. Isopropyl alcohol, 3.2 g/kg 24 h before N-nitrosodimethylamine, also increased these parameters 7-10-fold; this effect was associated with persistence of isopropyl alcohol and its metabolic product acetone, both IIE1 inhibitors, in the blood. While no N-nitrosodimethylamine was detected in expired air, trace amounts were found in urine. Ethanol and isopropyl alcohol pretreatment increased the maximum urinary N-nitrosodimethylamine concentration 15-50-fold and the percentage of the dose excreted in the urine by 100-800-fold. Thus ethanol and isopropyl alcohol greatly increase systemic exposure of extrahepatic organs to N-nitrosodimethylamine in a primate.

1-Propanol↗
PubMed1992

DNA adduct dosimetry and DNA repair in rats and pigs given repeated doses of procarbazine under conditions of carcinogenicity and human cancer chemotherapy respectively.

Procarbazine (PCZ), an antineoplastic agent that produces methylated bases in DNA after metabolic activation, has been implicated in the development of secondary cancers in patients treated for a primary neoplasm. The repair of the important promutagenic lesion, O6-methylguanine (O6-meG) by O6-alkylguanine-DNA alkyl transferase (AGT) is believed to be crucial for the stability of O6-meG and for the tumorigenic outcome after exposure to methylating carcinogens. Using two different animal models, we investigated methyl DNA adduct dosimetry and DNA repair in (i) female rats given repeated doses of PCZ for 20 weeks under conditions of carcinogenicity, and (ii) female pigs administered repeated doses of PCZ for 4 weeks according to a regimen comparable to that given to human subjects undergoing cancer chemotherapy. After each successive week, four rats and three pigs were killed and tissues including blood, liver, mammary gland, spleen, thymus and lymph node were taken. The levels of O6-meG, 7-methylguanine (7-meG) in DNA and of AGT were determined in these tissues. In the rat, O6-meG in the liver DNA, and to a lesser degree in the spleen was efficiently removed throughout the 20 week dosing period, as indicated by the O6-meG/7-meG ratio being much less than 0.11. In the target organs, accumulation of O6-meG began in the mammary gland after 9 weeks, and in the lymph node and thymus after 3 weeks of dosing. Interestingly, the accumulation of O6-meG in the mammary gland correlates well with a concomitant decrease in AGT level as from week 10 and may be related to the induction of mammary gland tumors, first detected in two animals at week 10. In pigs, after a total dose of 750-4000 mg of PCZ, the range of 7-meG detected in leukocyte DNA was 21-66 mumol/mol G, which compares well with recent findings in cancer patients treated with PCZ. Similar levels of 7-meG were detected in the pig liver, thymus and lymph node. O6-MeG was only detectable in leukocyte DNA at week 4 with our present method. Compared with control pig tissues, a depressed AGT level was found in the leukocyte, lymph node and brain of the treated animals.

Animals↗
PubMed1990

Interspecies scaling of the pharmacokinetics of N-nitrosodimethylamine.

The pharmacokinetics of N-nitrosodimethylamine was studied in patas monkeys following i.v. doses of 0.5, 1.0, and 5.0 mg/kg and a p.o. dose of 1.0 mg/kg, and in Swiss mice at i.v. doses of 1.0 and 2.0 mg/kg. In the patas monkey the pharmacokinetics was linear over the i.v. dose range studied. The mean clearance (Cl), steady-state volume of distribution (Vss), mean residence time, and elimination half-life (t 1/2) were 103.3 +/- 26.7 (SD) ml/min, 3061 +/- 821 ml, 30.8 +/- 10.8 min, and 21.1 +/- 8.5 min, respectively. Assuming that the pharmacokinetics was linear at the p.o. dose used, the p.o. bioavailability of N-nitrosodimethylamine in the monkey was 49%. The pharmacokinetics was also linear in mice, and the average Cl, Vss, mean residence time, and t 1/2 were 3.81 ml/min, 21.0 ml, 5.5 min, and 11.9 min, respectively. These data and data for rats, hamsters, rabbits, dogs, and pigs taken from the literature were used to scale Cl and Vss to body weight using the allometric equation. The resulting equation for Cl was Cl = 49.7B0.998 and the equation for Vss was Vss = 748B1.05 where B is body weight in kg. The fit of the data to the equation was excellent in both cases. Using these equations and assuming a body weight of 70 kg for humans, the Cl and Vss for N-nitrosodimethylamine in humans are estimated to be 3450 ml/min and 64,800 ml, respectively.

Animals↗
PubMed1990

Investigation into the effect of DHEA on renal carcinogenesis induced in the rat by a single dose of DMN.

Because long-term oral administration of the adrenal steroid dehydroepiandrosterone (DHEA) has previously been shown to inhibit the development of spontaneous breast cancer and chemically induced lung, colon, skin, and liver tumors in various mouse and rat strains, the effect of DHEA on the development of rat kidney tumors by a single dose of 30 mg/kg dimethylnitrosamine (DMN) was tested. DHEA was administered in the diet for a 26-week period commencing 2 weeks after DMN treatment. DHEA administration caused a reduction in body weight gain in accordance with its known antiobesity activity. However, it did not exert any inhibitory effect on either renal mesenchymal or cortical epithelial tumor induction by DMN, nor did it alter the average survival time. There was a statistically significant increase in the incidence of renal adenocarcinomas in the DHEA-treated group but not of renal adenomas. The results were discussed in relation to the mesodermal origin of kidney and the potency of single-dose systems of experimental cancer induction.

Adenocarcinoma↗
PubMed1990

DNA methyl-adduct dosimetry and O6-alkylguanine-DNA alkyl transferase activity determinations in rat mammary carcinogenesis by procarbazine and N-methylnitrosourea.

The metabolism of the carcinogenic antitumor drug procarbazine (PCZ) is complex with the ultimate production, among other metabolites, of a methyldiazonium ion which is also the ultimate carcinogenic species of the DNA-methylating N-nitroso compounds including N-methylnitrosourea (MNU). This suggests a similar mechanism of carcinogenic action. Following a single oral dose of [14C]PCZ (50 mg/rat) to 50 day old female Sprague-Dawley rats under the reported conditions of mammary gland carcinogenicity, the DNA adducts 7-methylguanine (7-meG) and O6-methylguanine (O6-meG) were determined in target (mammary gland) and non-target organs. The degree of DNA methylation was similar in all the organs considered. In the mammary gland, lung, spleen, small intestine and stomach the O6-meG/7-meG ratio was close to 0.11. At a lower dose of PCZ (26 mg/rat), the levels of 7-meG in the tissues were 40-60% of those produced by the higher dose. Eighty percent of the rats given the higher dose versus 37% of those given the lower dose developed mammary tumors after 20 weeks. With the higher dose of MNU (50 mg/kg body wt) DNA methylation was more or less uniform in all the organs including the mammary gland, with slightly greater yields in the liver. At a lower MNU dose (25 mg/kg) the levels of 7-meG were 40-48% of those produced by the higher dose. Fifty seven percent of the rats given the higher dose versus 21% of the animals given the lower dose developed mammary gland tumors after 20 weeks. On a mol/kg body wt basis, PCZ was approximately 5-times less active than MNU in the production of 7-meG in mammary gland but only approximately 2-times less active than MNU in the production of mammary gland tumors. The O6-alkylguanine-DNA alkyltransferase (AGT) levels in the liver, kidney, spleen and lung of PCZ or MNU treated rats were approximately 9-28% (expressed relative to protein content) and 10-33% (expressed relative to homogenate DNA content) of those in the corresponding organs of the saline-treated controls. However, the AGT levels of the mammary gland and brain were in the range of 45-61% (expressed relative to protein content) and 39-54% (expressed relative to homogenate DNA content) of those of the saline-treated controls. Also the mammary gland of the 50 day old female rats has the lowest AGT activity (expressed relative to DNA content).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Effect of short-term exposure of rats to dehydroepiandrosterone on the hepatic metabolism of dimethylnitrosamine.

The influence of short-term treatment with dehydroepiandrosterone (DHEA), a naturally occurring adrenal steroid, on hepatic metabolism and macromolecular interactions of the hepatocarcinogen dimethylnitrosamine (NDMA) was investigated in male Sprague-Dawley rats. Liver weight, total tissue protein (P less than 0.05), microsomal and cytosolic proteins and cytochrome P-450 (P less than 0.001) were all significantly increased in rats treated orally with DHEA (300 mg/kg body wt., suspended in 1.0 ml of sesame oil). The hepatic DNA content was not altered, however. Methylation of DNA by NDMA was reduced significantly in DHEA-treated rats (P less than 0.05). The binding of [14C]NDMA to hepatic proteins was greater in DHEA-treated rats. The results suggest that short-term treatment of rats with DHEA enhances the binding of NDMA-derived metabolites to hepatic proteins, resulting in the protection of DNA from the damaging effects of NDMA.

Animals↗
PubMed1989

Inhibition of methylation of DNA by dimethylnitrosamine (DMN) in dehydroepiandrosterone-fed rats.

The influence of the anticarcinogen dehydroepiandrosterone (DHEA) on the metabolism and macromolecular interactions of the potent hepatocarcinogen dimethylnitrosamine (NDMA) was investigated. Male Sprague-Dawley rats (2-3 mo old) were fed DHEA for 14 d at a dietary level of 0.8%. Compared with pair-fed controls, the liver weights of the DHEA-treated animals increased significantly (11.7 vs. 7.1 g) with increases, per total liver, in proteins including those of cytosol and microsomes as well as cytochromes P-450 and b5. DNA content of the liver, however, remained constant. Five hours after a single ip dose of [14C]NDMA (30 mg/kg body wt, 42 microCi/rat) DNA methylation was reduced in the DHEA-fed animals as measured by 7-methyl- and O6-methylguanine per mole of guanine, by 39 and 31%, respectively. The rate of NDMA metabolism was slightly higher in the DHEA-fed rats as determined in vivo by the exhalation of 14CO2 and by the declining concentrations of NDMA in the blood. The incorporation of radioactivity from [14C]NDMA into hepatic proteins in vivo was greater (2.1-fold) in the DHEA-fed rats. Our results suggest that feeding rats with the adrenal steroid DHEA enhances the metabolic activation of NDMA in vivo, and that the increased association of NDMA-derived metabolites with increased hepatic cellular proteins may be partially responsible for protection of hepatic DNA from NDMA-induced damage.

Animals↗
PubMed1989

Effect of dehydroepiandrosterone (DHEA) on the metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) in rats.

The influence of dehydroepiandrosterone (DHEA), an adrenal steroid, on the biotransformation of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) in rats has been investigated. Male Sprague-Dawley rats (2-3 months old) were fed DHEA for 14 days at a dietary level of 0.8%. There was an increase in liver weights with increases per whole liver, in total protein, microsomal and cytosolic protein and cytochrome P-450, and cytosolic glutathione transferase activity in DHEA fed rats. DNA content of the liver, however, remained constant. Forty-eight hours after a single i.p. dose of [3H]DMBA (133 mumol/kg body weight, 102 muCi/rat) binding of DMBA derived metabolites to DNA decreased significantly both per unit of DNA (605 versus 194 pmol/mg DNA) as well as per whole liver DNA (25.4 versus 8.5 nmol) in DHEA fed rats. However, a significantly higher amount of DMBA-derived metabolites were bound to total hepatic protein (455 versus 288 nmol) in the steroid fed rats. Microsome mediated binding of DMBA to DNA was 3-fold higher in DHEA fed rats. Excretion of DMBA-derived metabolites in urine was 2-fold higher in DHEA fed rats. The results of this study demonstrate that DHEA inhibits binding of DMBA to hepatic DNA in vivo in spite of the increased metabolic activation of the carcinogen perhaps due to increased detoxification and competitive binding of its active species to proteins.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Pharmacokinetics of N-nitrosodimethylamine in swine.

The pharmacokinetics of N-nitrosodimethylamine (NDMA) have been studied in swine. They were studied following i.v. administration of 0.1, 0.5 and 1.0 mg/kg, and following oral doses of 1.0 and 5.0 mg/kg of NDMA. Following a bolus i.v. dose, the concentration of NDMA in blood declined biphasically with a mean distribution half-life of 7 min and a mean elimination half-life of 28 min. The areas under the blood concentration versus time curves (AUC) were roughly proportional to dose indicating that the pharmacokinetics in this dose range were first order. The mean systemic clearance from blood was 65.8 ml/min/kg, the steady-state volume of distribution was 1.4 l/kg, and the mean residence time was 20 min. Following the oral doses, the AUC and peak concentration in blood were not proportional to the dose. It is likely that the pharmacokinetics at the lower dose were first order, but at the higher dose the pharmacokinetics were no longer first order because metabolism was saturated. The bioavailability of the 1.0 mg/kg dose was 67%. Since the clearance was probably due to metabolism and the clearance from blood exceeded hepatic blood flow, the high bioavailability suggests that extrahepatic metabolism plays an important role in the systemic clearance of NDMA in swine.

Animals↗
PubMed1988

Deregulation and overexpression of c-fos proto-oncogene in rat renal cell-lines and primary tumors induced by dimethylnitrosamine.

Rat renal mesenchymal tumors induced by the chemical carcinogen N-dimethylnitrosamine (DMN) and cell-lines derived from kidneys of rats after DMN treatment were found to express abnormal steady state levels of c-fos RNA. This overexpression was not found to arise by gene amplification or rearrangement, but the c-fos gene appeared to be deregulated resulting in increased transcription. The consistent nature of this observation suggests a function for c-fos gene overexpression in tumorigenesis of the rat kidney by DMN.

Animals↗
PubMed1987

Effect of glutathione modulation using buthionine sulfoximine on DNA methylation by dimethylnitrosamine in the rat.

An in vivo study was carried out in order to determine whether glutathione (GSH) might serve as a scavenger for the supposed electrophilic methylating fragment derived from dimethylnitrosamine (DMN) and thus function to decrease the degree of cellular macromolecule interaction, estimated by measuring the DNA methylation yield. After a 4-hr pretreatment with DL-buthionine-SR-sulfoximine (BSO), a specific inhibitor of GSH synthesis, male Sprague-Dawley rats were dosed with radiolabeled DMN (250 micrograms/kg). Four hours later the animals were killed and the livers and kidneys were excised. The DNA isolated from these organs was hydrolyzed in mild acid, and the liberated purines were quantified utilizing HPLC and liquid scintillation counting. The 70-75% GSH depletion in the liver and kidney resulting from BSO pretreatment did not have any significant effect on the degree of DNA methylation as assessed by the 7-methylguanine/guanine yield. In control experiments we found that DMN doses greater than 1 mg/kg had a marked effect on liver and kidney GSH levels after 4 hr.

Animals↗
PubMed1987

Evidence for metabolism of N-nitrosoproline.

The metabolism of nitrosoproline (NPRO) was re-investigated in uni- and bilaterally nephrectomized rats that have reduced or absent ability to excrete urine. About 1% of the administered radioactivity from L-[U-14C]-NPRO appeared as 14CO2 in the expired air and the production of 14CO2 was time-dependent over a period of 23 h. As compared with sham-operation, uni- or bilateral nephrectomy did not significantly increase the amount of NPRO metabolism, though urinary excretion of radioactivity was decreased in the unilaterally nephrectomized animals. In microsome-mediated and in vitro enzyme-free (Udenfriend-hydroxylating) systems covalent binding of [2,3,4,5-3H]NPRO to exogenous calf thymus DNA was demonstrated. The above findings confirm that in vivo metabolism of NPRO is possible, albeit, to a very small extent.

Animals↗
PubMed1987

Effect of (+)-catechin, dimethyl sulfoxide and ethanol on the microsome-mediated metabolism of two hepatocarcinogens, N-nitrosodimethylamine and aflatoxin B1.

Effects of catechin, a plant phenolic flavonoid, and of the commonly used organic solvents dimethyl sulfoxide (DMSO) and ethanol (EtOH) on the microsome-mediated metabolism of two hepatocarcinogens, N-nitrosodimethylamine (NDMA) and aflatoxin B1 (AFB1), are presented. Using hamster liver microsomes as a source of mixed-function oxidases, it was shown that catechin at 0.1-0.2 mM levels had no effect on the oxidation of either carcinogen. However, at 1-5 mM levels it caused a concentration-dependent inhibition (38-70%) of the formation of formaldehyde from NDMA, and at the 5 mM level it caused a 40% inhibition of AFB1-DNA binding. DMSO and EtOH totally inhibited NDMA demethylase activity but had little effect on the binding of AFB1 to DNA. These observations indicate that the mixed-function oxidases (cytochrome P450) essential for the metabolic activation of these carcinogens exhibit different sensitivities to different inhibitors.

Aflatoxin B1↗