PubMed Health⌕ Search

Biomedical subjects

T F McMahon

Publications and source records attributed to T F McMahon.

14 recordsLinked to original sources
PubMed1992

The effects of age on the pharmacokinetics and biotransformation of theophylline in vivo and in vitro in the Mongolian gerbil (Meriones unguiculatus).

The effect of post maturational aging on the in vivo disposition of theophylline was examined in the Mongolian gerbils (Meriones unguiculatus) aged 30-39 (old), 12-18 (middle-aged) and 3 (young) months following a 20 mg/kg i.p. dose. Biotransformation of theophylline was also examined in liver microsomes from non-induced and 3-methylcholanthrene induced gerbils. Analysis of theophylline plasma kinetics showed decreased clearance, increased half-life and increased volume of distribution in old vs. young animals. Clearance to the 1,3-dimethyluric acid metabolite was similar for all age groups, while clearance to the 1-methyluric acid metabolite was significantly lower in the middle-aged group compared to that of young and old gerbils. Urinary recovery of 1-methylurate was increased in old vs. young and middle-aged animals while recovery of theophylline was decreased. 3-Methylcholanthrene induction resulted in decreased recovery of theophylline and increased recovery of 1,3-dimethylurate and 1-methylurate in young and middle-aged gerbils compared to non-induced controls. Decreased microsomal protein content was observed in old vs. young and middle-aged gerbils and an age-related decrease in cytochrome P-450 content (nmol P-450/g liver) was also observed. The rate of dimethylurate formation was decreased 37% in microsomes from old vs. young and middle-aged gerbils. 3-Methylcholanthrene administration resulted in a 2- and 1.5-fold increase in the rate of 1,3-dimethylurate formation in young and middle-aged gerbils, respectively. The results of these experiments indicate that the Mongolian gerbil may be useful for the study of the biochemical mechanisms underlying age-related changes in the biotransformation and kinetics of theophylline.

Aging↗
PubMed1991

Comparative acute nephrotoxicity of salicylic acid, 2,3-dihydroxybenzoic acid, and 2,5-dihydroxybenzoic acid in young and middle aged Fischer 344 rats.

Experimental evidence suggests that the oxidative metabolites 2,3- and 2,5-dihydroxybenzoic acid (DIOH) may be responsible for the nephrotoxicity of salicylic acid (SAL). In the present study, enzymuria in conjunction with glucose (GLU) and protein (PRO) excretion were used as endpoints to compare the relative nephrotoxicity of SAL with 2,3- and 2,5-DIOH. In addition, the effect of age on enzymuria and GLU and PRO excretion following treatment with SAL or 2,3- and 2,5-DIOH was investigated because the elderly are at greater risk for SAL-induced nephrotoxicity. Three and 12-month male Fischer 344 rats were administered either no treatment, vehicle, SAL, 2,3-DIOH, or 2,5-DIOH at 500 mg/kg p.o. in 5 ml/kg corn oil/DMSO (5:1). Effects of these treatments on functional integrity of renal tissue was assessed from 0--72 h after dosing by measurement of urinary creatinine, GLU, and PRO, as well as excretion of proximal and distal tubular renal enzymes. Enzymes measured as indicators of proximal tubular damage were N-acetyl-beta-glucosaminidase (NAG), gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), and alkaline phosphatase (AP), while urinary lactate dehydrogenase (LD) and aspartate aminotransferase (AST) were measured as indicators of distal tubular damage. In comparison to 3-month vehicle-treated rats, 2,3- and 2,5-DIOH caused a significant increase between 0-8 h in excretion of urinary GLU and activities of AST, NAG, and LD, with peak effects occurring between 4-8 h. Toxic effects of either metabolite were not evident beyond 24 h, and toxicity of 2,5-DIOH was significantly greater in comparison to 2,3-DIOH. SAL treatment resulted in similar effects on enzymuria as well as GLU and PRO excretion, but peak effects did not occur until 16-24 h, and often persisted until 72 h after dosing. Maximal enzymuria in response to SAL treatment was significantly greater in 12- vs. 3-month rats for AST, NAG, and LD. In response to 2,3-DIOH treatment, the maximal response was significantly greater in 12- vs. 3-month rats for LD and AST, and for NAG in response to 2,5-DIOH treatment. The results of this study suggest that both 2,3- and 2,5-DIOH are nephrotoxic metabolites of SAL, but implicate 2,5-DIOH as the more potent nephrotoxic metabolite. The relative lack of an age effect for 2,3- and 2,5-DIOH vs. SAL supports the hypothesis [2] that age-related differences in biotransformation of SAL, and not increased tissue sensitivity to 2,3- or 2,5-DIOH, contribute to the age-related increase in susceptibility to SAL-induced nephrotoxicity.

Acetylglucosaminidase↗
PubMed1991

Mutagenicity of methylazoxymethanol acetate in the presence of alcohol dehydrogenase, aldehyde dehydrogenase, and rat liver microsomes in Salmonella typhimurium His G46.

Methylazoxymethanol (MAM) is the short-lived toxic and carcinogenic aglycone of cycasin, a natural component of the cycad plant. In the present study, the stable acetate ester of MAM, MAM acetate, was tested in combination with porcine liver esterase and Salmonella typhimurium His G46 to study the comparative mutagenicity of this compound in the presence of rat hepatic alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and rat liver microsomes. In the presence of rat liver microsomes and an NADPH-generating system, mutagenicity of MAM acetate was not significantly altered. However, addition of rat liver 105,000g supernatant fraction and/or NAD+ significantly increased the number of his+ revertants above control. A concentration-dependent increase in mutagenicity of MAM acetate was observed for NAD+ from 50 to 200 microM, while NADP+ caused a decrease in mutagenicity of MAM acetate in this same concentration range. Pyrazole (100-500 microM) had no significant effect on mutagenicity of MAM acetate in the presence of rat liver 105,000g supernatant, while disulfiram at 500 microM resulted in a significant decrease in mutagenicity of MAM acetate. The results of this study implicate ALDH as essential in activation of MAM acetate to a mutagenic species in this system, while the role of ADH and microsomes appears to be minimal.

Alcohol Dehydrogenase↗
PubMed1990

Age-related changes in toxicity and biotransformation of potassium cyanide in male C57BL/6N mice.

Age-related changes in toxicity and biotransformation of KCN, an ubiquitous environmental toxicant, have not been previously examined. Male C57BL/6N mice aged 2-3 (young), 10-12 (middle-aged), and 25-30 (old) months were administered KCN at 1, 2, 4, and 6 mg/kg po, and toxic manifestations were monitored for up to 2 hr. The toxic response to KCN (prostration and labored breathing) was significantly greater in 10-12 and 25-30 month vs that in 2-3 month mice at 4 and 6 mg/kg KCN. The basis for this age-related difference in in vivo toxicity was examined by studying biotransformation of KCN to thiocyanate by liver and brain rhodanese (RHO), as well as activity of liver and brain cytochrome oxidase (C-OX), inhibition of C-OX by KCN, and activity of beta-mercaptopyruvate transsulfurase (MT). Tissue and blood levels of CN- following a toxic dose of 6 mg/kg KCN were also measured. No age-related differences were observed in the specific activity of liver and brain RHO, MT, or C-OX. In addition, no differences were observed in the percentage inhibition of C-OX by KCN, or in the Ki for inhibition of brain and liver C-OX. However, activity of brain RHO on a per gram tissue basis was significantly lower in 10-12 and 25-30 months vs that in 2-3 month mice. Liver and blood concentrations of CN- were not significantly different in 2-3 vs 10-12 month mice following treatment with 6 mg/kg KCN; however, significantly greater concentrations of CN- were observed at 4 and 25 min in brains of 10-12 month mice compared to that in 2-3 month mice. These results indicate that increased sensitivity to KCN in older mice may be due in part to a decrease in the amount of brain RHO and altered tissue kinetics of CN- following a toxic dose in older mice.

Aging↗
PubMed1990

Age-related changes in biotransformation of azoxymethane and methylazoxymethanol in vitro.

1. Age-related changes in hepatic hydroxylation of azoxymethane (AZO) to methylazoxymethanol (MAM), as well as colonic phase I metabolism of MAM by alcohol dehydrogenase (ADH) were examined in young (2-4 months), middle-aged (12-14 months), and old (22-24 months) male Fischer 344 rats. In addition, the possibility that colonic glucuronyltransferase might be involved in the biotransformation of MAM was also investigated. 2. A significant decrease in hepatic conversion of AZO to MAM was found in old vs young rats, concomitant with a decrease in hepatic cytochrome P-450 content, while no age-related difference was found in the colonic metabolism of MAM by ADH. MAM inhibition of colonic 4-methylumbelliferone glucuronyltransferase was non-competitive, suggesting indirectly that colonic glucuronyltransferase is not involved in conjugation of MAM. 3. It is concluded that ageing in the male Fischer 344 rat results in alternations of AZO and MAM biotransformation which indicate that AZO may be less carcinogenic in older rats.

Aging↗
PubMed1987

Effects of age on antidepressant kinetics and memory in Fischer 344 rats.

Experiments were conducted in young (3-4 months) and old (24-25 months) male Fischer 344 rats to assess the effects of amitriptyline, scopolamine, and zimelidine on short term memory using an eight arm radial maze paradigm. Kinetic analyses employing serial blood sampling were also conducted for amitriptyline and zimelidine in an attempt to determine if age-related deficits in performance could be related to changes in pharmacokinetics. In the maze, acquisition of performance was significantly decreased in old rats compared to young. Amitriptyline (5 mg/kg) produced a significant decrement in maze performance on day four of a five day testing period in both young and old rats, while scopolamine (1 mg/kg) produced an initial decrement on day one, followed by a return towards pre-treatment levels in these two age groups. Zimelidine (5 mg/kg) produced no performance decrement in either young or old rats. Kinetic analyses revealed an increased half-life, slower plasma clearance, and a larger volume of distribution of amitriptyline and zimelidine in old rats. Although the kinetic parameters in aged rats exhibited a change in the direction of a decreased ability to metabolize both drugs, this change was not of sufficient magnitude to produce an additive detrimental effect on maze performance.

Aging↗
PubMed1987

Changes in phase I and phase II biotransformation with age in male Fischer 344 rat colon: relationship to colon carcinogenesis.

Using male Fischer 344 rats classified as young (2-4 months), middle aged (12-14 months), and old (22-25 months), the activities of several Phase I and Phase II biotransformation pathways in the large intestine were investigated, including benzo[a]pyrene hydroxylase (BPOH), alcohol dehydrogenase (ADH), glutathione S-transferase (GST), glutathione peroxidase (GSH-PX), beta-glucuronidase (BG), and microsomal and nuclear glucuronyltransferase (UDPGT). Levels of oxidized (GSSG) and reduced (GSH) glutathione and uridine 5'-diphosphoglucuronic acid (UDPGA) were also measured. BPOH increased 33% in old rats, while ADH and BG activity remained unchanged with age. Nuclear UDPGT remained unchanged with age, whereas form I of GSH-PX declined slightly in old rats. GST, microsomal UDPGT, and form II of GSH-PX declined by 38, 37 and 44%, respectively, in old rats. The decrease in GST and microsomal UDPGT was also significant in middle aged rats. Levels of colonic GSH, GSSG and UDPGA were found to be unchanged with age. These in vitro data suggest the possibility that if reactive intermediates are generated to the same extent in old rats as in young rats, decreased detoxification mechanisms in the old rat may increase susceptibility of the colon to actions of chemical carcinogens.

Aging↗
PubMedDate not supplied

Age-related changes in disposition and metabolism of benzene in male C57BL/6N mice.

Benzene disposition and metabolism were examined as a function of age in male C57BL/6N mice aged 3 and 18 months. Mice received a single oral dose of either 10 or 200 mg/kg 14C-benzene (approximately 25 microCi/kg). Excretion of 14C-derived benzene radioactivity (RA) was monitored in urine, feces, and as exhaled 14CO2 from 0 to 72 hr, and as exhaled unmetabolized benzene from 0 to 6 hr. At 10 mg/kg 14C-benzene, urinary elimination was the major route of excretion in both 3- and 18-month mice. Urinary excretion of 14C-derived benzene RA was significantly decreased in 18- vs. 3-month mice at 4, 6, 24, and 48 hr, while fecal excretion was significantly increased at 72 hr. Elimination of 14C-benzene as 14CO2 and unmetabolized 14C-benzene was also increased in 18- vs. 3-month mice at this dose. Hydroquinone glucuronide (HQG), phenylsulfate (PS), and muconic acid (MUC) were the major urinary metabolites at 10 mg/kg 14C-benzene in both 3- and 18-month mice, representing approximately 40, 28, and 15% of an administered dose of 14C-benzene. Smaller amounts of phenyl glucuronide (4.0%), pre-phenyl mercapturic acid (1.2%), and catechol glucuronide (0.5%) were also detected. No significant differences were found with age in the percentage of an administered dose of benzene excreted as the various metabolites at 10 mg/kg. At 200 mg/kg 14C-benzene, the total percentage of 14C-derived benzene RA eliminated in urine within 72 hr was not significantly different with age, but elimination at early time points (4, 6, and 8 hr) was significantly decreased in 18- vs. 3-month mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMedDate not supplied

Effects of age and dose on disposition and metabolism of salicylic acid in male Fischer 344 rats.

Salicylic acid (SAL)-induced nephrotoxicity has been reported to be greater in older rats. To examine age- and dose-related changes in disposition and metabolism, male Fischer 344 rats aged 3, 12, and 25 months were administered single doses of 14C-SAL at 5,50, and 500 mg/kg po. At 5 mg 14C-SAL/kg, urinary excretion of 14C-SAL derived radioactivity (RA) followed first-order kinetics and was complete by 24 hr in 3- and 25-month-old rats, but not until 48 hr in 12-month-old rats. The percentage of administered 14C-SAL excreted as the oxidative metabolites 2,3- and 2,5-dihydroxybenzoic acid (2,3- and 2,5-diOH), unmetabolized SAL, or salicyl ester glucuronide (SA-AG) was unchanged with age. The percentage excreted as the ether glucuronide (SA-PC) was significantly decreased in 25-month-old rats, while the percentage excreted as the glycine conjugate, salicyluric acid (SUA) was significantly increased in 12- and 25-month-old rats. At 50 mg SAL/kg, urinary elimination shifted toward zero-order kinetics and was not complete until 48 hr in all age groups. The percentage of an administered dose of 14C-SAL found in urine as 2,3- and 2,5-diOH and SA-AG increased significantly in all age groups, while the percentage excreted as SUA decreased significantly. Twelve- and 25-month-old rats excreted a significantly greater percentage of the total dose as 2,3- and 2,5-diOH than 3-month-old rats at this dose. No SA-PG was detected at this dose in any age group. At 500 mg SAL/kg, mortality was observed in both 3- and 25-month-old rats and excretion of SAL-derived RA in urine was incomplete at 48 hr. However, data indicated a further shift in biotransformation toward increased production of oxidative metabolites and a decrease in SUA production. No significant overall differences were observed between 3- and 25-month-old rats in plasma levels of 14C-SAL following iv administration of 5 and 50 mg SAL/kg. However, elimination half-life (t1/2) was significantly increased in 25-month-old rats at 5 mg SAL/kg vs. 3-month-old rats. These results indicate that the age-related increase in acute nephrotoxicity of SAL may result from increased production of oxidative metabolites in older rats at higher doses of SAL.

Aging↗
PubMedDate not supplied

Age-related changes in the disposition of benzyl acetate. A model compound for glycine conjugation.

The in vivo metabolism and excretion of benzyl acetate (BA), a model compound for glycine conjugation, was examined in male Fischer 344 rats and C57BL/6N mice. Rats aged 3-4, 9, and 25 months received a single oral dose of either 5 or 500 mg/kg 14C-BA, while male mice aged 2, 13, and 25 months received a single oral dose of 10 mg/kg 14C-BA. Urine and feces were collected for 96 hr. Biliary excretion and plasma elimination were also examined in male Fischer rats after iv administration of 5 mg/kg 14C-BA. In both young and old rats and mice, hippuric acid (HA) was the major urinary metabolite after oral dosing of BA. No significant age-related difference was observed in rats in the urinary elimination of BA-derived radioactivity or in the percentage of the total dose excreted as hippuric acid (approximately 95%). Twenty-five-month old rats excreted a significantly higher percentage of the total dose as benzyl mercapturic acid (approximately 2%) than did 3- to 4-month-old rats (approximately 1%) at the 5 mg dose. Benzyl mercapturic acid excretion in 3- to 4-month-old rats was also increased significantly at 500 mg/kg BA vs. 5 mg/kg BA. Fecal excretion of BA-derived radioactivity declined significantly in 25-month-old rats at both the 5 and 500 mg dose. This decrease was reflected by an age-related decline in biliary excretion and higher plasma levels of BA-derived radioactivity. Examination of plasma metabolites revealed a significantly higher level of HA and benzoyl glucuronide in 25-month rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗