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Results for “Enzyme Induction”

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PubMed1986

Insulin-like growth factor I regulation of transcription and replicating enzyme induction necessary for DNA synthesis.

Insulin-like growth factor I (IGF-I) regulation of the sequence of transcriptional, translational, and postranslational events during G1 that are necessary for DNA synthesis, and the induction of thymidine kinase and in vivo thymidylate synthase activities was studied in synchronized confluent BALB/c 3T3 mouse fibroblasts. IGF-I was the only growth factor necessary from 6 to 2 1/2 hours before S phase for onset of DNA synthesis. 5,6 dichlororibofuranosylbenzimidazole (DRB), an inhibitor of transcription, was ineffective in blocking DNA synthesis and increase of both enzyme activities during an interval of about 2 1/2 hours before S phase. Cycloheximide, an inhibitor of translation, was ineffective in blocking DNA synthesis and the increase of in vivo thymidylate synthase activity during an interval of about 1 1/2 hours before S phase but was effective in blocking the increase of thymidine kinase activity up to the G1/S boundary. The results demonstrate that IGF-I is dispensable beyond the R-point (2-3 hours before S phase), the time when serum factors are no longer necessary for the initiation of DNA synthesis, and that IGF-I regulates transcriptional events necessary for both DNA synthesis and the induction of thymidine kinase and in vivo thymidylate synthase. The results also demonstrate a posttranslational interval for in vivo thymidylate synthase, suggesting posttranslational modification of this enzyme.

Animals↗
PubMed1976

Effects of enzyme induction and inhibition on microsomal oxidation of 1,4-benzodiazepines.

Metabolic oxidative profiles of diazepam (I) were obtained by aromatic C-4'-hydroxylation, N-1-demethylation, and 3-hydroxylation using a supernatant of rat liver. Incubation of 3-methyldiazepam (VI), which suppressed 3-hydroxylation, and N-1-nor-3-methyldiazepam (VII), were used to separately investigate these three oxidative pathways. Treatment of animals with phenobarbital enhanced N-1-demethylation and 3-hydroxylation, and to a variable extent C-4'-hydroxylation. Application of metyrapone reduced metabolite formation by 3-hydroxylation and N-1-demethylation, but had no effect on C-4'-hydroxylation. Metyrapone inhibition was more pronounced following than prior to phenobarbital treatment. C-2-hydroxylation was studied using medazepam (XX) incubations. This pathway was increased by phenobarbital pretreatment and reduced by metyrapone inhibition which was again more pronounced following than prior to phenobarbital pretreatment. These results support earlier conclusions on the heterogeneity of liver microsomes and suggests the presence of different species of hepatic microsomal terminal oxidases. Phenobarbital treatment and metyrapone change the metabolic profile via induction and inhibition, respectively, and, thus, in the case of 1,4-benzodiazepines, the formation of metabolites with varying pharmacological activity. This could become important in clinical situations as a diagnostic mean to determine induction under various treatment or, possibly, during cumulation of metabolites with a long half-life.

Animals↗
PubMed1990

Aminoglutethimide enzyme induction: pharmacological and endocrinological implications.

Aminoglutethimide is an aromatase inhibitor that is successfully used for endocrine treatment of advanced breast cancer. This drug also stimulates the activity of hepatic mixed-function oxidases, increasing the metabolism of several drugs, including warfarin, digitoxin, antipyrine and theophylline. It also increases the plasma clearance rate of oestrone sulphate. As this oestrogen may be an important substrate for tumour cells, stimulation of oestrone sulphate metabolism may be a component of the mechanism of action of aminoglutethimide.

Aminoglutethimide↗
PubMed2003

A phase II detoxification enzyme inducer from lemongrass: identification of citral and involvement of electrophilic reaction in the enzyme induction.

We have developed a simple system for the sensitive detection and measurement of glutathione S-transferase (GST) activity that detoxifies polycyclic aromatic hydrocarbons using the cultured rat normal liver epithelial cell line, RL34 cells. Citral (3,7-dimethyl-2,6-octadienal) was isolated from the methanol extract of lemongrass (Cymbopogon citratus) and identified as a novel inducer of GST. Citral, a mixture of the two stereoisomers geranial and neral, dose- and time-dependently induced the total and pi-class-specific activities of GST. The structure-activity relationship study revealed that geranial, an E-isomer, was mainly responsible for the inducing activity of citral mixture and the aldehyde group conjugated with a trans-double bond is an essential structural factor. The data were consistent with the in vitro observation that both glutathione (GSH) and protein thiol quickly and specifically reacted with the active isomer geranial, but not neral. Pretreatment of the cells with diethyl maleate significantly enhanced not only the basal activity but also the citral-stimulated activity of GST, while pretreatment with N-acetyl-cysteine inhibited it. Moreover, the treatment of RL 34 cells with geranial for 30 min significantly attenuated the intracellular GSH level, while application for 18 h enhanced it. These results strongly suggested that the electrophilic property characterized by the reactivity with intracellular nucleophiles including protein thiol or glutathione (GSH) plays an important role in the induction of GST. The present study also implied the antioxidant role of GST induction by citral in mouse skin, providing a new insight into skin cancer prevention.

Animals↗
PubMed2003

Impact of adolescent nicotine exposure on adenylyl cyclase-mediated cell signaling: enzyme induction, neurotransmitter-specific effects, regional selectivities, and the role of withdrawal.

Recent animal studies indicate that the adolescent brain is especially vulnerable to nicotine-induced alterations in synaptic function, echoing the increased susceptibility to nicotine dependence and withdrawal noted for adolescent smokers. We administered nicotine to adolescent rats via continuous minipump infusions from PN30 to PN47.5, using 6 mg/kg/day, a dose rate that replicates the plasma nicotine levels found in smokers, and examined the effects on cell signaling mediated through adenylyl cyclase (AC) and its response to catecholamines. Studies were conducted during nicotine administration (PN45) and in the posttreatment, withdrawal period (PN50, 60, 75). Adolescent nicotine augmented AC activity as evidenced by increased responsiveness to the direct AC stimulants, forskolin and Mn(2+). The effects on AC were equally noted in brain regions enriched (striatum) or sparse (cerebellum) in cholinergic projections, implying that the effects are secondary to activation/repression of neural circuits, rather than representing direct effects on AC mediated by nicotinic cholinergic receptors. AC responses to dopaminergic and noradrenergic stimulants were also enhanced by nicotine exposure. However, in contrast to earlier work with serotonin-mediated responses, the effects on catecholaminergic stimulation were smaller and did not display the sex-dependence noted for serotonin. An alternate administration paradigm that maximizes episodic withdrawal (twice-daily nicotine injections) induced AC more rapidly at lower nicotine doses. Our results indicate that adolescent nicotine exposure elicits lasting alterations in synaptic signaling that intensify and persist during withdrawal. These findings support the concept that the adolescent brain is especially susceptible to persistent nicotine-induced alterations.

Adenylyl Cyclases↗
PubMed1998

Gut wall metabolism of verapamil in older people: effects of rifampicin-mediated enzyme induction.

AIMS: To investigate prehepatic metabolism of verapamil and its inducibility by rifampicin in older subjects. METHODS: Eight older subjects (67.1 +/- 1.2 years mean +/- s.d.) received racemic, unlabelled verapamil orally for 16 days (120 mg twice daily). Rifampicin (600 mg daily) was coadministered from day 5 to 16. Using stable isotope technology (i.e. intravenous coadministration of 10 mg deuterated verapamil) during verapamil steady-state without (day 4) and with rifampicin (day 16) bioavailability, prehepatic and hepatic extraction of verapamil were determined. The effects of verapamil on AV-conduction were measured by the maximum PR interval prolongation (%). RESULTS: Bioavailability of the cardiovascularly more active S-verapamil decreased from 14.2 +/- 4.3% on day 4 to 0.6 +/- 0.5% on day 16 (P < 0.001). As a consequence, effects of orally administered verapamil on the AV-conduction were nearly abolished (14.4 +/- 9.4% vs 2.7 +/- 2.6%, P < 0.01). This could be attributed to a considerable increase of prehepatic extraction during treatment with rifampicin (41.7 +/- 22.1% vs 91.6 +/- 6.6%, P < 0.01) and to a minor extent to induction of hepatic metabolism (73.7 +/- 9.4% vs 91.6 +/- 5.3%, P < 0.01). CONCLUSIONS: Prehepatic metabolism of verapamil occurred in the group of older people investigated. Induction of gut wall metabolism most likely was the major reason for the loss of verapamil effect during treatment with rifampicin in this group of older subjects.

Aged↗