scholarly journals Metabolism of six CYP probe substrates in fetal hepatocytes

ADMET & DMPK ◽  
2016 ◽  
Vol 4 (2) ◽  
pp. 84 ◽  
Author(s):  
Abdul Naveed Shaik ◽  
Sandeep Kumar Vishwakarma ◽  
Aleem A Khan
Keyword(s):  
Isolated Hepatocytes ◽  
Drug Metabolizing Enzymes ◽  
Human Foetus ◽  
Metabolizing Enzymes ◽  
Expression Levels ◽  
Physiological Conditions ◽  
Fetal Hepatocytes ◽  
Disease States ◽  
Common Drug ◽  
Cytochrome P 450

<p class="ADMETabstracttext">Cytochrome P-450 (CYP) are the most common drug metabolizing enzymes and are abundantly expressed in liver apart from kidney, lungs, intestine, brain etc. Their expression levels change with physiological conditions and disease states. The expression of these CYPs is less in human foetus and neonates compared to adults, which results in lower clearance of xenobiotics in infants and neonates compared to adults. Hepatocytes are the cells which are largely used to study these CYPs. We have isolated hepatocytes from aborted foetus to study the metabolism of six probe substrates: phenacetin, diclofenac, S-mephenytoin, dextromethorphan, nifedipine and testosterone. The results obtained show the expression of various CYPs (CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4) in human foetus and their involvement in metabolism of CYP probe substrates.</p>

scholarly journals A Pilot Study towards the Impact of Type 2 Diabetes on the Expression and Activities of Drug Metabolizing Enzymes and Transporters in Human Duodenum

2019 ◽  
Vol 20 (13) ◽  
pp. 3257 ◽  
Author(s):  
Sophie Gravel ◽  
Benoit Panzini ◽  
Francois Belanger ◽  
Jacques Turgeon ◽  
Veronique Michaud
Keyword(s):  
Type 2 Diabetes ◽  
Mrna Expression ◽  
Drug Metabolizing Enzymes ◽  
Mrna Levels ◽  
Metabolizing Enzymes ◽  
Expression Levels ◽  
The Impact ◽  
Duodenal Biopsies ◽  
Mrna Expression Levels

To characterize effects of type 2 diabetes (T2D) on mRNA expression levels for 10 Cytochromes P450 (CYP450s), two carboxylesterases, and three drug transporters (ABCB1, ABCG2, SLCO2B1) in human duodenal biopsies. To compare drug metabolizing enzyme activities of four CYP450 isoenzymes in duodenal biopsies from patients with or without T2D. mRNA levels were quantified (RT-qPCR) in human duodenal biopsies obtained from patients with (n = 20) or without (n = 16) T2D undergoing a scheduled gastro-intestinal endoscopy. CYP450 activities were determined following incubation of biopsy homogenates with probe substrates for CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2J2 (ebastine), and CYP3A4/5 (midazolam). Covariables related to inflammation, T2D, demographic, and genetics were investigated. T2D had no major effects on mRNA levels of all enzymes and transporters assessed. Formation rates of metabolites (pmoles mg protein−1 min−1) determined by LC-MS/MS for CYP2C9 (0.48 ± 0.26 vs. 0.41 ± 0.12), CYP2J2 (2.16 ± 1.70 vs. 1.69 ± 0.93), and CYP3A (5.25 ± 3.72 vs. 5.02 ± 4.76) were not different between biopsies obtained from individuals with or without T2D (p > 0.05). No CYP2B6 specific activity was measured. TNF-α levels were higher in T2D patients but did not correlate with any changes in mRNA expression levels for drug metabolizing enzymes or transporters in the duodenum. T2D did not modulate expression or activity of tested drug metabolizing enzymes and transporters in the human duodenum. Previously reported changes in drug oral clearances in patients with T2D could be due to a tissue-specific disease modulation occurring in the liver and/or in other parts of the intestines.

Effects of chronic ethanol administration in the rat: relative dependency on dietary lipids. II. Paradoxical role of linoleate in the induction of hepatic drug-metabolizing enzymes in vitro

1977 ◽  
Vol 55 (1) ◽  
pp. 34-41 ◽  
Author(s):  
Jean-Gil Joly ◽  
Claude Hétu
Keyword(s):  
Dietary Lipid ◽  
Dietary Lipids ◽  
Chronic Ethanol ◽  
Ethanol Administration ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Drug Biotransformation ◽  
Chronic Ethanol Administration ◽  
Cytochrome P 450

The effect of chronic ethanol administration on the hepatic microsomal cytochrome P-450 content and activities of NADPH – cytochrome P-450 reductase (EC 1.6.2.4), benzphetamine demethylase, aniline hydroxylase (EC 1.14.14.1), and of the microsomal ethanol-oxidizing system were studied in various dietary models. When ethanol was given with linoleate as the only source of dietary lipid, the ethanol induction of these parameters was greater with diets containing 2 or 5% of total calories as linoleate than with diets containing 10% of total calories as linoleate. By contrast, when ethanol was given with high fat (35% of total calories) diets, the ethanol induction of these same parameters was slightly greater when linoleate provided 10% of total calories than when it provided 3% of calories. The apparent effect of dietary linoleate on the induction, by ethanol, of microsomal drug-metabolizing enzymes is markedly different when linoleate is given as the only source of dietary lipid as opposed to when it is given with other dietary lipids. Thus, conclusions on the effect of ethanol on hepatic microsomal drug-biotransformation enzymes, drawn from studies with dietary models in which linoleate provides the only source of dietary lipid, cannot be extended to dietary models of more complex lipid composition. When given as the only source of lipid, 2% of total calories in linoleate appears optimal for basal activity and inductibility, by ethanol, of mixed-function oxidases.

scholarly journals The effects of chemical porphyrogens and drugs on the activity of rat liver tryptophan pyrrolase

1973 ◽  
Vol 136 (4) ◽  
pp. 885-892 ◽  
Author(s):  
Abdulla A.-B. Badawy ◽  
Myrddin Evans
Keyword(s):  
Mental Disorders ◽  
Rat Liver ◽  
Daily Injection ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Tryptophan Pyrrolase ◽  
Cytochrome P 450 ◽  
Subsequent Administration

1. Drugs such as phenobarbitone and phenylbutazone, which increase the concentration of microsomal haem and cytochrome P-450, also increase the saturation of rat liver apo-(tryptophan pyrrolase) with its haem activator, as does the haem precursor 5-aminolaevulinate. 2. At 4h after the administration of the porphyrogens 2-allyl-2-isopropylacetamide, 3,5-diethoxycarbonyl-1,4-dihydrocollidine and griseofulvin, the total pyrrolase activity is increased whereas the haem saturation of the apoenzyme is decreased. This decreased saturation is prevented by pretreatment of the animals with the inhibitor of drug-metabolizing enzymes, SKF 525-A. 3. Pretreatment of rats with the above porphyrogens inhibits the rise in holo-(tryptophan pyrrolase) activity produced by subsequent administration of cortisol, tryptophan and 5-aminolaevulinate with two single exceptions, the possible reasons for which are discussed. 4. At 24h after the administration, in starved rats, of a single daily injection of the above porphyrogens for 1 or 2 days, the holoenzyme activity is significantly increased. 5. It is suggested that the saturation of rat liver apo-(tryptophan pyrrolase) with its haem activator can be modified by treatment known to cause destruction, inhibition of synthesis, increased utilization and enhanced synthesis of liver haem. The possible involvement of the latter phenomenon in the aetiology of mental disorders in some patients with porphyria is discussed.

scholarly journals The Effect of Psoralens on Hepatic and Cutaneous Drug Metabolizing Enzymes and Cytochrome P-450

1982 ◽  
Vol 79 (3) ◽  
pp. 201-205 ◽  
Author(s):  
David R. Bickers ◽  
Hasan Mukhtar ◽  
S.J. Molica ◽  
Madhu A. Pathak
Keyword(s):  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Cytochrome P 450

Polymorphisms in drug-metabolizing enzymes as modifiers of cancer risk

1995 ◽  
Vol 41 (12) ◽  
pp. 1864-1869 ◽  
Author(s):  
N K Spurr ◽  
A C Gough ◽  
F I Chinegwundoh ◽  
C A Smith
Keyword(s):  
Colon Cancer ◽  
Bladder Cancer ◽  
General Population ◽  
Cancer Risk ◽  
Gene Product ◽  
Drug Metabolizing Enzymes ◽  
Polymorphic Variation ◽  
Metabolizing Enzymes ◽  
Low Penetrance Genes ◽  
Cytochrome P 450

Abstract The identification of low-penetrance genes, the polymorphisms of which increase an individual's risk of developing cancer, are likely to be extremely important in the general population. In this report we analyzed two genes involved in detoxification. In a number of loci, we identified polymorphic variation correlating with the expression of the gene product. We analyzed two such loci, the cytochrome P-450 gene CYP2D6 and the N-acetyltransferase 2 (NAT2) genes, in patients with bladder and colon cancer, respectively. We observed no statistically significant associations between the control and cancer populations; however, there was a small increase in heterozygote number in bladder cancer.

The Effects of Pretreatment of Mice with Norethindrone on the Metabolism of 14C-imipramine by the Liver Microsomal Drug-Metabolizing Enzymes

1974 ◽  
Vol 52 (1) ◽  
pp. 28-38 ◽  
Author(s):  
G. D. Bellward ◽  
R. G. Morgan ◽  
V. H. Szombathy
Keyword(s):  
Female Mouse ◽  
Mouse Liver ◽  
Competitive Inhibition ◽  
Drug Metabolizing Enzymes ◽  
Concurrent Administration ◽  
Metabolizing Enzymes ◽  
Assay Procedure ◽  
Cytochrome P 450 ◽  
Enzyme Source

An assay procedure for the metabolism of 14C-imipramine in vitro is described. Using female mouse liver as the enzyme source, the conditions of the assay have been determined for the formation of 2-hydroxyimipramine, desmethylimipramine, and imipramine-N-oxide. Demethylation was linear up to a substrate concentration of 120 μg/3.5 ml, N-oxidation was linear up to a concentration of imipramine of 70 μg/3.5 ml, and hydroxylation up to 20 μg/3.5 ml of reaction mixture. Desmethylimipramine competitively inhibited both hydroxylation and demethylation, whereas imipramine-N-oxide had no effect. Pretreatment of mice with norethindrone decreased hydroxylation, and increased demethylation. Cytochrome P-450 was also increased by this progestin; N-oxidation was not changed. The effects of concurrent administration of norethindrone with known inducers or inhibitors of drug metabolism have been determined. From these experiments, it was concluded that the induction of cytochrome P-450 by norethindrone is not responsible for the increased demethylation of imipramine. Rather, it appeared that competitive inhibition of hydroxylation of imipramine by the norethindrone allowed more of the drug to be demethylated.

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