Effect of chronic cysteamine treatment on mouse liver aryl hydrocarbon hydroxylase activity

1988 ◽  
Vol 66 (11) ◽  
pp. 1433-1436 ◽  
Author(s):  
Theresa C. Peterson
Keyword(s):  
Nephropathic Cystinosis ◽  
Aryl Hydrocarbon Hydroxylase ◽  
Serum Aminotransferase ◽  
Aryl Hydrocarbon ◽  
Human Dose ◽  
Aryl Hydrocarbon Hydroxylase Activity ◽  
In Vivo Effects ◽  
Cytochrome P 450

Patients receive chronic cysteamine in the management of nephropathic cystinosis. In a previous report our results indicated that acute cysteamine treatment inhibited cytochrome P-450. Cysteamine (85 mg/kg i.p.) was administered daily to female Swiss mice for 1.5 and 8.5 months. Cysteamine treatment (8.5 months) did not affect hepatic microsomal aryl hydrocarbon hydroxylase (AHH) activity compared with controls. A small decrease in liver AHH activity was seen after 1.5 months of treatment with cysteamine. Liver histology, body weight, liver and spleen weights, and serum aminotransferase activity after chronic and subchronic treatment did not differ from controls. Chronic in vivo cysteamine treatment, unlike acute in vitro treatment did not decrease AHH activity. Incubation of isolated murine hepatocytes with cysteamine significantly inhibited AHH activity compared with controls. The inhibition occurred in a concentration-related manner, with 65% inhibition at 8.8 mM (1 mg/mL) (equivalent to the predicted plasma concentration using the maximally tolerable human dose), and 100% inhibition at 44 mM (5 mg/mL). The concentrations used in vitro were not cytotoxic. This suggests that chronic cysteamine treatment may not result in drug interactions and that in vitro results are not always good indicators of in vivo effects.

Stimulation of iron absorption by polychlorinated aromatic hydrocarbons.

1979 ◽  
Vol 236 (6) ◽  
pp. E763
Author(s):  
J Manis ◽  
G Kim
Keyword(s):  
Aromatic Hydrocarbons ◽  
Iron Transport ◽  
Major Effect ◽  
Aryl Hydrocarbon Hydroxylase ◽  
Aryl Hydrocarbon ◽  
Tcdd Treatment ◽  
Aryl Hydrocarbon Hydroxylase Activity ◽  
Intraperitoneal Treatment ◽  
Polychlorinated Aromatic Hydrocarbons

Oral and intraperitoneal treatment of rats with a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 33 microgram/kg, causes a 41--67% increase in iron adsorption in vivo. The major effect is on the transfer of iron from the mucosa into the bloodstream rather than on the uptake of iron from the lumen of the gut. These results are confirmed in studies with everted gut sacs. The effect is maximal at 1--2 days with a dose of 22-42 microgram/kg. Calcium transport is inhibited by TCDD treatment, whereas galactose and proline transport are unaffected. Treatment of rats with 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane also stimulates iron transport. Concomitant with iron transport stimulation, aryl hydrocarbon hydroxylase activity in the intestine and liver is increased by TCDD treatment. These studies suggest that polychlorinated aromatic hydrocarbons, which are environmental health hazards, may effect the intestinal absorption of essential mineral nutrients.

Alterations of Hepatic Microsomal Drug Metabolism by Glucagon

1975 ◽  
Vol 53 (5) ◽  
pp. 873-879 ◽  
Author(s):  
Jacob V. Aranda ◽  
Kenneth W. Renton
Keyword(s):  
Substrate Oxidation ◽  
Type I ◽  
Nadph Cytochrome ◽  
Transport Chain ◽  
Hexobarbital Sleeping Time ◽  
Nadph Oxidation ◽  
In Vivo Effects ◽  
Cytochrome P 450

The effect of glucagon on the components of the hepatic microsomal electron transport chain (NADPH oxidase, NADPH cytochrome c reductase (EC 1.6.2.4), cytochrome P-450, and NADPH cytochrome P-450 reductase), and on two representative oxidative pathways (aminopyrine N-demethylation, a type I substrate oxidation; and aniline p-hydroxylation, a type II substrate oxidation) was determined. Microsomes from rats pretreated with glucagon (300 μg/kg per day for 3 days) showed a significant decrease in NADPH oxidation and in aminopyrine N-demethylation with a prolonged hexobarbital sleeping time, and a significant increase in aniline p-hydroxylation. Microsomes from rats pretreated with a lower dose of glucagon (30 μg/kg per day for 3 days) showed a significant decrease in the microsomal N-demethylation of aminopyrine. Glucagon had no effect when added in vitro to microsomes, suggesting that the in vivo effects of glucagon are mediated indirectly in the intact animal.

scholarly journals Isolation and characterization of revertants from four different classes of aryl hydrocarbon hydroxylase-deficient hepa-1 mutants.

1984 ◽  
Vol 4 (8) ◽  
pp. 1597-1604 ◽  
Author(s):  
J R Van Gurp ◽  
O Hankinson
Keyword(s):  
Enzyme Stability ◽  
Ah Receptor ◽  
Wild Type ◽  
Aryl Hydrocarbon Hydroxylase ◽  
Gene Group ◽  
Aryl Hydrocarbon ◽  
Isolation And Characterization ◽  
Dominant Mutant

Revertants were selected from aryl hydrocarbon hydroxylase (AHH)-deficient recessive mutants belonging to three complementation groups and from a dominant mutant of the Hepa-1 cell line. The recessive mutants had low spontaneous reversion frequencies (less than 4 X 10(-7] that were increased by mutagenesis. The majority of these revertants also had reacquired only partial AHH activity. Revertants of group A mutants were identical to the wild type with respect to both in vivo and in vitro enzyme stability and the Km for the substrate, benzo [alpha]pyrene, and therefore failed to provide evidence that gene A is the AHH structural gene. Group B and group C mutants are defective in the functioning of the Ah receptor required for AHH induction. Revertants of these groups were normal with respect to in vivo temperature sensitivity for AHH induction and for the 50% effective dose for the inducer, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and thus provided no evidence that the B and C genes code for components of the receptor. Two rare group C revertants possessed AHH activity in the absence of induction. The phenotype of one of these was shown to be recessive to the wild type. Spontaneous revertants of the dominant mutant occurred at a frequency 300-fold greater than those of the recessive mutants, and this frequency was not increased by mutagenesis. These revertants all displayed complete restoration of AHH activity to wild type levels. These observations and the results from cell hybridization studies suggest that the dominant revertants arose by a high frequency event leading to functional elimination of the dominant mutation.

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