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Biomedical subjects

H M Carpenter

Publications and source records attributed to H M Carpenter.

33 records · Page 2Linked to original sources
PubMed1984

Hexachlorobenzene-induced porphyria in Japanese quail. Effect of pretreatment with phenobarbital or beta-naphthoflavone.

In an effort to determine the role that metabolism by the cytochrome P-450 system plays in the development of hexachlorobenzene (HCB)-induced porphyria, Japanese quail were pretreated with either beta-naphthoflavone (BNF) or phenobarbital (PB) and then treated with HCB. PB or BNF pretreatment appeared to have no effect on the response of quail hepatic enzymes to HCB. There were no differences between the two groups in either the content of cytochrome P-450 or the activities of NADPH-cytochrome c reductase, glutathione transferase (microsomal or cytosolic), ethoxycoumarin-O-deethylase or ethoxyresorufin-O-deethylase following HCB treatment. These pretreatments did, however, markedly influence the development of porphyria in quail. BNF-treated birds had higher delta-aminolevulinic acid-synthetase (ALA-S) activities and developed porphyria much more rapidly than birds treated with HCB alone. Birds pretreated with PB did not exhibit porphyria even following 10 days of HCB. Although the ALA-S activities in this group were elevated slightly following HCB, they were about one-half of those seen in the BNF-pretreated HCB-treated group. These results may reflect a difference between the PB and BNF groups in the production of a porphyrogenic metabolite of HCB.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1983

Differential induction of hepatic drug metabolizing enzymes in Japanese quail by 1,2,4-trichlorobenzene.

The effects of single oral administration of 1,2,4-trichlorobenzene (TCB), 200, 400, 800 or 1600 mg/kg, and of daily oral administration of TCB, 400 mg/kg, for 3 consecutive days, on components of the microsomal monooxygenase system, glutathione, and the activities of cytosolic glutathione S-transferase and microsomal epoxide hydrolase in Japanese quail liver were studied. Cytochromes P-450 and b5 contents of liver microsomes and the activities of 7-ethoxyresorufin deethylase (7-ERD) and glutathione S-transferase were significantly increased 1 day after administration of single doses of TCB. Liver GSH and 7-ethoxycoumarin deethylase (7-ECD) activity were unchanged. Microsomal epoxide hydrolase activity was significantly decreased at TCB doses above 400 mg/kg. Increases in cytochromes and activities of 7-ERD and glutathione S-transferase were also seen following the 3-day administration of TCB, 400 mg/kg. In addition, liver GSH and the activity of NADPH-cytochrome c reductase were significantly increased whereas 7-ECD was significantly decreased by the 3-day treatment. These findings indicate that in Japanese quail, TCB is an inducer of 7-ERD and glutathione S-transferase but not of 7-ECD and epoxide hydrolase.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1983

Studies on the porphyrinogenic action of 1,2,4-trichlorobenzene in birds.

The porphyrinogenic action of 1,2,4-trichlorobenzene (TCB) was examined in 17-day-old embryos, day-old chicks, 18-day-old chickens and adult Japanese quail. The quail was found to be the most sensitive species towards TCB induced porphyria whereas the chick embryo was totally non-responsive. The liver porphyrins of Japanese quail were increased in a dose-dependent manner 1 day after TCB. Elevation in porphyrin levels in quail was associated with comparable increases in delta-aminolevulinic acid synthetase (ALA-S) activity 1 day after TCB treatment. In contrast, ferrochelatase activity was found to be unchanged 1 day after TCB. Multiple administration of TCB produced only a slight increase in liver porphyrin levels and ALA-S activity in quail. However, there was a marked induction in ferrochelatase activity suggesting increased porphyrin turnover. Liver glutathione and glutathione S-transferase activity were also significantly increased following repeated administration of TCB in quail, which could indicate an enhancement of detoxication of reactive metabolites of TCB. Thus, it is suggested that the inability of low multiple doses of TCB to cause porphyria in Japanese quail may be related to the low responsiveness of ALA-S but high inducibility of ferrochelatase liver GSH and glutathione S-transferase.

Animals↗
PubMed1981

Acetaminophen nephrotoxicity: studies on renal acetylation and deacetylation.

Acetaminophen (N-acetyl-p-aminophenol; APAP) inhibits both the acetylation and uptake of p-aminohippurate (PAH) by slices of mouse kidney cortex; p-aminophenol (PAP) is more potent than APAP in inhibiting the acetylation of PAH, but has no effect on uptake of PAH. Since PAP itself is acetylated by the kidney, the action of PAP on the acetylation of PAH might be competitive. However, from kinetic analysis the inhibition is principally noncompetitive in nature. In studies on deacetylation, PAP was generated from APAP both in slices and homogenates of kidneys; acetylated PAH was relatively stable. PAP is a known nephrotoxin but has not been identified previously as a metabolite of APAP. The data indicate that the kidney has the capacity to generate a potent nephrotoxin, PAP, from a relatively benign precursor, APAP. This potentiality should be considered in further studies on the pathogenesis of analgesic nephropathy.

Acetaminophen↗
PubMed1980

Uptake and acetylation of p-aminohippurate by slices of mouse kidney cortex.

In slices of mouse kidney cortex, p-aminohippurate (PAH) is taken up by the organic anion transport system and then rapidly acetylated to p-acetylaminohippurate acid (PAAH), so that there is little net accumulation of PAH itself. The basic characteristics of this system have been described. Uptake may be measured as the total of PAH and PAAH combined. Both uptake and acetylation are dependent on aerobic metabolism. Succinate strongly inhibits net accumulation but has only a slight effect on the amount acetylated. This is attributed to the stimulation of efflux by succinate. In the mouse, the degree of acetylation as well as uptake varies with sex and strain, as well as with the drug used as substrate. When organic anion transport is employed as a test system for the assay of nephrotoxicity, it is proposed that slices from the mouse possess advantages over some other species in that acetylation and uptake provide dual endpoints.

Acetylation↗
PubMedDate not supplied

Low dose chlordecone pretreatment altered cholesterol disposition without induction of cytochrome P-450.

Pretreatment of mice with low doses of chlordecone (CD) alters the pattern of distribution of a subsequent tracer dose of [14C]CD. We call this preexposure effect a pretreatment disposition response (PDR) and suggest that it reflects important cellular responses to lipophilic compounds. The present study examined three possible mechanisms for CD-induced PDR (CD-PDR). The first was that CD-PDR occurred with induction of the cytochrome P-450 system. A cumulative dose of 45 mg/kg CD caused a PDR, increased the content of cytochrome P-450, and elevated the activities of ethoxyresorufin- and ethoxycoumarin-O-deethylases (EROD and ECOD). A cumulative dose of 10 mg/kg caused a PDR, but did not affect cytochrome P-450, EROD, or ECOD, indicating that an induction of the cytochrome P-450 system in not necessary for PDR. A second possibility examined was that CD-PDR resulted because of an altered affinity of a subcellular fraction. Following a pretreatment regimen designed to produce PDR, amounts of [14C]CD in each fraction paralleled homogenate values in the liver and the kidney. However, when values were calculated as percentages of total label recovered, it was apparent that [14C]CD levels were higher in the microsomal fraction of the liver. Finally, the possibility that CD-PDR occurred because of an interaction of CD with proteins involved in cholesterol synthesis and transport was addressed. CD pretreatment increased disposition of a dose of [14C]cholesterol to the fat at the expense of [14C]cholesterol in the liver and kidney.

Animals↗
PubMedDate not supplied

A characterization of chlordecone pretreatment-altered pharmacokinetics in mice.

Lipophilic chlorinated hydrocarbons pose a potential health hazard to humans and animals and the toxicity of a number of these compounds has been well documented. Despite the low environmental concentrations of most of these chemicals, much of the research conducted to date has used maximally tolerated doses. Our research, conducted with low, apparently nontoxic, doses of the insecticide chlordecone (CD), showed that the administration of CD (5 mg/kg ip) to mice (C57BL/6N and DBA/2N strains) caused a time-dependent alteration in the pattern of distribution of a subsequently administered dose of [14C]CD. Livers of CD-pretreated animals contained less label than did those from controls and CD pretreatment increased amounts of label in kidney, lung, fat, and muscle. Changes did not appear to be due to an altered rate of metaboLism and analysis of total CD in tissues (unlabeled plus [14C]CD) indicated that these responses were not due to a simple redistribution phenomenon. We have termed this preexposure effect a pretreatment disposition response (PDR) and feel it may reflect an important cellular response to lipophilic compounds. CD-induced PDR is dose related, exhibits a threshold, and is saturable at a given level of induction. In addition, PDR exhibits some specificity, inasmuch as pretreating mice with CD (5 mg/kg) does not alter the distribution of subsequently administered [14C]dieldrin. The characteristics of threshold, saturability, and specificity are consistent with the premise that CD-induced PDR is a protein-mediated phenomenon.

Animals↗