Induction Of Cytochrome P450 Isoenzymes Research Articles

Alcohol as a risk factor for drug-induced diseases

Administration of a rational and safe drug therapy is one of the most challenging issues for healthcare professionals. The frequency of hospitalizations due to the adverse drug reactions in the years 2000 — 2015 was estimated at 6.3 (3.3—11.0 %) for developed countries and 5.5 % (1.1—16.9 %) for developing countries. It is known that alcohol intake is a risk factor for many socially significant diseases, including arterial hypertension, coronary heart disease, chronic heart failure, etc., however, many doctors pay insufficient attention to the fact that many drugs, for example, beta-blockers, antidepressants, bezodisepines, calcium antagonists, can interact with alcohol when consumed simultaneously and, thus, increase the risks of adverse drug reactions. There are 2 main types of interactions between alcohol and drugs: pharmacokinetic (at the stage of absorption, distribution, metabolism and elimination) and pharmacodynamic (at the stage of effects and receptors). For example: the simultaneous intake of alcohol and paracetamol leads to the formation of toxic metabolites due to the induction of cytochrome P450 isoenzymes by alcohol. Another example is decrease in presystemic elimination and stimulation of the metabolism of tricyclic antidepressants; an increase in the elimination of imipramine and desipramine in patients with chronic alcoholism after detoxification therapy, and so on. In this article, the authors analyzed and systematized data from open literature sources in order to inform health care professionals about the possible risks associated with the interaction of alcohol and drugs and various pharmacological groups.

The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism.

Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities.

Impacto de diferentes medicamentos antiepilépticos na sedação de crianças durante a ressonância magnética

Background and objectivesThe induction and inhibition of cytochrome P450 isoenzymes by antiepileptic drugs lead to changes in the clearance of anesthetic drugs eliminated via hepatic metabolism. We investigated the duration of the sedation and additional anesthetic needs during magnetic resonance imaging in epileptic children receiving antiepileptic drugs that cause either enzyme induction or inhibition. MethodsIn American Society of Anesthesiology I–II, 120 children aged 3–10 years were included. Group 1: children using antiepileptic drugs that cause cytochrome P450 enzyme induction; Group 2: those using antiepileptic drugs that cause inhibition; and Group 3: those that did not use antiepileptic drugs. Sedation was induced with the use of 0.05 mg kg−1 midazolam and 1 mg kg−1 propofol. An additional 0.05 mg kg−1 of midazolam and rescue propofol (0.5 mg kg−1) were administered and repeated to maintain sedation. The duration of sedation and the additional sedation needed were compared. ResultsThe duration of the initial dose was significantly shorter in Group I compared with groups II and III (p = 0.001, p = 0.003, respectively). It was significantly longer in Group II compared with groups I and III (p = 0.001, p = 0.029, respectively). The additional midazolam needed for adequate sedation was increased in Group I when compared with groups II and III (p = 0.010, p = 0.001, respectively). In addition, the rescue propofol dose was significantly higher only in Group I when compared with Group III (p = 0.002). ConclusionIn epileptic children, the response variability to the initial sedative agents during the magnetic resonance imaging procedure resulting from the inhibition or induction of the cytochrome P450 isoenzymes by the antiepileptic drugs mandated the titration of anesthetic agents.

Impacto de diferentes medicamentos antiepilépticos en la sedación de niños durante la resonancia magnética

Background and objectivesThe induction and inhibition of cytochrome P450 isoenzymes by antiepileptic drugs lead to changes in the clearance of anesthetic drugs eliminated via hepatic metabolism. We investigated the duration of the sedation and additional anesthetic needs during magnetic resonance imaging in epileptic children receiving antiepileptic drugs that cause either enzyme induction or inhibition. MethodsIn American Society of Anesthesiology I–II, 120 children aged 3–10 years were included. Group 1: children using antiepileptic drugs that cause cytochrome P450 enzyme induction; Group 2: those using antiepileptic drugs that cause inhibition; and Group 3: those that did not use antiepileptic drugs. Sedation was induced with the use of 0.05 mg kg−1 midazolam and 1 mg kg−1 propofol. An additional 0.05 mg kg−1 of midazolam and rescue propofol (0.5 mg kg−1) were administered and repeated to maintain sedation. The duration of sedation and the additional sedation needed were compared. ResultsThe duration of the initial dose was significantly shorter in Group I compared with groups II and III (p = 0.001, p = 0.003, respectively). It was significantly longer in Group II compared with groups I and III (p = 0.001, p = 0.029, respectively). The additional midazolam needed for adequate sedation was increased in Group I when compared with groups II and III (p = 0.010, p = 0.001, respectively). In addition, the rescue propofol dose was significantly higher only in Group I when compared with Group III (p = 0.002). ConclusionIn epileptic children, the response variability to the initial sedative agents during the magnetic resonance imaging procedure resulting from the inhibition or induction of the cytochrome P450 isoenzymes by the antiepileptic drugs mandated the titration of anesthetic agents.

The impact of different antiepileptic drugs on the sedation of children during magnetic resonance imaging

Background and objectivesThe induction and inhibition of cytochrome P450 isoenzymes by antiepileptic drugs lead to changes in the clearance of anesthetic drugs eliminated via hepatic metabolism. We investigated the duration of the sedation and additional anesthetic needs during magnetic resonance imaging in epileptic children receiving antiepileptic drugs that cause either enzyme induction or inhibition. MethodsIn American Society of Anesthesiology I–II, 120 children aged 3–10 years were included. Group 1: children using antiepileptic drugs that cause cytochrome P450 enzyme induction; Group 2: those using antiepileptic drugs that cause inhibition; and Group 3: those that did not use antiepileptic drugs. Sedation was induced with the use of 0.05mgkg−1 midazolam and 1mgkg−1 propofol. An additional 0.05mgkg−1 of midazolam and rescue propofol (0.5mgkg−1) were administered and repeated to maintain sedation. The duration of sedation and the additional sedation needed were compared. ResultsThe duration of the initial dose was significantly shorter in Group I compared with groups II and III (p=0.001, p=0.003, respectively). It was significantly longer in Group II compared with groups I and III (p=0.001, p=0.029, respectively). The additional midazolam needed for adequate sedation was increased in Group I when compared with groups II and III (p=0.010, p=0.001, respectively). In addition, the rescue propofol dose was significantly higher only in Group I when compared with Group III (p=0.002). ConclusionIn epileptic children, the response variability to the initial sedative agents during the magnetic resonance imaging procedure resulting from the inhibition or induction of the cytochrome P450 isoenzymes by the antiepileptic drugs mandated the titration of anesthetic agents.

A review of the evidence concerning hepatic glutathione depletion and susceptibility to hepatotoxicity after paracetamol overdose.

Paracetamol (acetaminophen) poisoning is common throughout the world. The management of nonstaggered (acute) paracetamol overdose is based on the plasma paracetamol concentration plotted on a treatment nomogram. In the UK there are two treatment lines on this nomogram, with the lower treatment line used for individuals felt to be at ‘high risk’ of paracetamol-related hepatotoxicity either as a result of induction of cytochrome P450 isoenzymes or reduction of intrahepatic glutathione. In this article we review the risk factors that, in current guidelines, are felt to increase risk due to a reduction in intrahepatic glutathione concentrations. Based on our review of the published literature, we feel that cystic fibrosis, acute viral illness, malnutrition, and eating disorders such as anorexia nervosa are likely to be associated with reduction in intrahepatic glutathione concentrations, and that this risk is likely to be related to malnutrition secondary to the disease. Chronic hepatitis C infection is also associated with reduced glutathione concentrations, although this appears to be independent of any associated malnutrition. Ageing and acute fasting are not associated with an increased risk of paracetamol-related hepatotoxicity due to reductions in glutathione concentrations. Finally, the evidence for HIV infection is inconclusive, particularly as the majority of studies were conducted in the pre-anti-viral treatment (HAART) era; however it is likely that patients with symptomatic HIV/AIDS have reduced glutathione concentrations due to associated malnutrition. Although there have been few studies which have specifically investigated whether there is an association between reduced intrahepatic glutathione concentrations and increased risk of paracetamol-related hepatotoxicity, in our opinion, it is likely that the above conditions that are associated with reduced glutathione concentrations, will be associated with an increased risk of paracetamol-related hepatotoxicity.

Testosterone hydroxylases in evaluating induction of cytochrome P450 isoenzymes by pyrethroids Type II deltamethrin and cyfluthrin

Testosterone hydroxylases in evaluating induction of cytochrome P450 isoenzymes by pyrethroids Type II deltamethrin and cyfluthrin

Efavirenz and Rifampicin in the South African Context: Is There a Need to Dose-Increase Efavirenz with Concurrent Rifampicin Therapy?

Increasing efavirenz (EFV) dose from 600 mg to 800 mg daily has been suggested with concomitant rifampicin (RFN), as induction of cytochrome P450 isoenzymes may reduce EFV plasma concentrations. Individuals from the CIPRA-South Africa cohort taking EFV-based antiretroviral therapy with concomitant tuberculosis (TB) were dosed with either increased (800 mg) or standard (600 mg) dose EFV during TB treatment. After TB therapy, all individuals took 600 mg EFV. Two mid-dosing interval EFV concentrations were determined from each individual: after 4 weeks of concomitant EFV and RFN therapy, and ≥4 weeks after TB therapy completion. Mid-dosing interval EFV concentrations were compared within individuals using the Wilcoxon signed-rank test. Paired samples were collected from 72 individuals. Overall, 45 (63%) were women and median weight was 59 kg (IQR 52-67). At antiretroviral therapy start, median CD4(+) T-cell count was 114 cells/mm(3) (IQR 37-165), median viral load was 5.5 log (IQR 5.1-5.9). A total of 38 (53%) individuals took 800 mg EFV during TB treatment and 34 (47%) took 600 mg. EFV concentrations in the 800 mg group were higher with RFN (2.9 mg/l [IQR 1.8-5.6]) than without (2.1 mg/l [IQR 1.4-3.0]; P=0.0003). There was no significant difference in EFV concentrations with RFN (2.4 mg/l [IQR 1.2-5.1]) or without (2.2 mg/l [IQR 1.4-3.7]) in the 600 mg group. There was no increase in EFV-linked adverse effects in either group. The proportion of virologically suppressed individuals at 48 weeks was similar in both groups. EFV concentrations were significantly increased in the EFV 800 mg group on RFN. There was no significant decrease in EFV concentrations when on RFN in the 600 mg group. Dose escalation of EFV 600 mg to 800 mg is not required during concomitant TB therapy in South Africa.

Expression and Induction of Cytochrome P450 Isoenzymes in Human Skin Equivalents

Organotypic skin models are frequently used for a wide range of applications and latterly also for dermatotoxicological studies. To evaluate their practicability for the investigation of xenobiotic metabolism in human skin we compared three types of organotypic skin models, acquired by purchase from different manufacturers, to a self-constructed in-house model with regard to cytochrome P450 (CYP) isoenzyme expression on mRNA and protein level and the inducibility of these enzymes by aryl hydrocarbon receptor ligands. To induce enzyme activity, models were treated with benzanthracene, liquor carbonis detergens, pix lithanthracis or dimethyl sulfoxide as a solvent control. RNA was isolated by phenol-chloroform extraction and purified. Gene expression patterns were studied by cDNA microarray analysis. Microarray data were confirmed by real-time PCR. For quality control of the models and to detect and localize enzyme expression, immunofluorescence staining was performed with antibodies against CYPs and structure proteins. The immunofluorescence staining demonstrated the regular structure of our models. We could provide evidence for the expression of CYP types 1A1, 1B1, 2E1, 2C and 3A5 in organotypic skin models. The expression of CYP1A1 and CYP1B1 was highly inducible by treatment with liquor carbonis detergens. The proof of the expression and inducibility of CYP enzymes in organotypic skin models suggests that skin equivalents are a valuable tool that can emulate CYP-dependent metabolism of drugs and other xenobiotics in human skin.

PMH15 ANALYSIS OF POTENTIAL DRUG-DRUG INTERACTION PAIRS ASSOCIATED WITH ANTIPSYCHOTICS AMONG MEDICAID PATIENTS WITH SCHIZOPHRENIA OR BIPOLAR DISORDER

Objectives: Patients with schizophrenia, schizoaffective disorder, or bipolar disorder often receive multiple medications as part of their treatment regimens. Since many antipsychotics are metabolized by cytochrome P450 (CYP450) isoenzymes (1A2, 2D6, and 3A4), we proposed to assess the risk of receiving potential drug-drug interaction (DDI) pairs associated with the inhibition or induction of CYP450 isoenzymes.

Induction of CYP isoenzymes in various organs of rats by 3-methylcholanthrene or beta-naphthoflavone.

Induction of cytochrome P450 (CYP) isoenzymes in various organs of rats treated with 3-methylcholanthrene (3-MC) and beta-naphthoflavone (BNF) was immunohistochemically and biochemically investigated. Fifteen male F344 rats were divided into three equal groups. Group 1 was untreated as a control. On days 3, 4, 13 and 14, group 2 animals received 3-MC (20 mg/kg body wt i.p.) dissolved in corn oil while group 3 animals were given BNF (50 mg/kg body wt i.p.) dissolved in corn oil, at days 1, 2, 3, 4, 11, 12, 13 and 14. On days 4 and 14, two or three animals in each group were sacrificed, 15 h after administration of the last test compound. Induction of CYP 1A1, 2C11, 2D1, 2E1, 3A2 and 4A1 in various organs was immunohistochemically examined and the levels of CYP 1A1 protein were measured by Western blotting. 3-MC and BNF induced CYP isoenzymes not only in the liver, but also in the small intestine, large intestine, prostate and seminal vesicles. The results indicate that xenobiotic metabolism can occur in various organs.

Induction of Cytochrome P450 Isoenzymes after Toxicokinetic Interactions between 2,3,7,8-Tetrachlorodibenzo- p-dioxin and 2,2′,4,4′,5,5′-Hexachlorobiphenyl in the Liver of the Mouse

Induction of Cytochrome P450 Isoeuzymes after Toxicokinetic Interactions between 2,3,7,8-Tetrachlorodibenzo- p-dioxin anti 2,2′,4,4′,5,5′-Hexachlorobiphenyl in the Liver of the Mouse. De Jongh, J., Devito, M., Nieboer, R., Birnbaum, L., and Van den Berg, M. (1995). Fundam. Appl. Toxicol. 25, 264-270. One group of male C57BL/6J mice received a single oral dose of 1 nmol 2,3.7,8-tetrachlorodibenzo- p-dioxin (TCDD)/kg. Six other groups received single oral doses of 100, 300, or 1000 μamol 2,2′,4,4′,5,5′-hexachlorobipheoyl (HxCB)/kg, alone or in combination with 1 nmol/kg TCDD. Liver deposition of both compounds was studied at Day 3 after dosage. Hepatic CYP1A1 and CYP1A2 protein levels and related 7-ethoxyresorufin-O-deethylation (EROD) and acetanilide 4-hydroxylation (ACOH) activities were also studied. A significant increase in the hepatic deposition of TCDD was observed in all three mixed dose groups but TCDD did not influence hepatic HxCB deposition. TCDD did increase both CYP1A1 and CYP1A2 protein levels. In the HxCB-treated groups, CYP1A2 levels were also increased in a dose-dependent way but CYP1A1 levels were not increased. CYP1A2 activities (ACOH), but not protein levels, in the TCDD groups cotreared with HxCB were higher than those in the group treated will TCDD alone. CYP1A1-dependent EROD activity and CYP1A2-dependent ACOH activity were induced in all treated dose groups. It is concluded that the present results do not confirm a direct role of CYP1A2 induction in the increase of hepatic TCDD levels by HxCB cotreatment in the mixed HxCB/TCDD dose groups. However, in this aspect, the discrepancy between CYP1A2 activities and protein levels remains to be explained.

Induction of Cytochrome P-450 isoenzymes in cultured monkey hepatocytes

The effect of phenobarbital (PB), β-naphthoflavone (β-NF) and rifampicin (Rif) on the drug-metabolizing activity of cultured squirrel monkey hepatocytes was examined. The drug metabolizing activity (e.g. alkoxycoumarin dealkylase or steroid hydroxylase) gradually decreased during the culture period with 40–70% activity remaining at 72 hr. When 0.5 mM PB was added to the culture, the activities of 7-methoxycoumarin O-demethylase (MCOD) and 7-ethoxycoumarin O-deethylase (ECOD) increased to 6–7 fold higher level than those of control at 72 hr. Testosterone 6β-hydroxylase (6β-OH-T) and testosterone 16β-hydroxylase (16β-OH-T) activities were approx. 3-fold higher than those of the control. Addition of β-NF significantly increased the activities of 7-ethoxyresorufin O-deethylase (EROD) and ECOD. Though statistically insignificant, Rif slightly increased 6β-OH-T activity. Western blot analysis indicated PB induced production of the CYP 2B and 3A subfamilies, while β-NF and Rif induced that of the CYP 1A and the CYP 3A subfamily, respectively.

Induction of Cytochrome P450 Isoenzymes after Toxicokinetic Interactions between 2,3,7,8-Tetrachlorodibenzo-p-dioxin and 2,2′,4,4′,5,5′-Hexachlorobiphenyl in the Liver of the Mouse

One group of male C57BL/6J mice received a single oral dose of 1 nmol 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg. Six other groups received single oral doses of 100, 300, or 1000µmol 2,2′,4,4′,5,5′-hexachlorobiphenyl (HxCB)/kg, alone or in combination with 1 nmol/kg TCDD. Liver deposition of both compounds was studied at Day 3 after dosage. Hepatic CYP1A1 and CYP1A2 protein levels and related 7-ethoxyres-orufin-O-deethylation (EROD) and acetanilide 4-hydroxylation (ACOH) activities were also studied. A significant increase in the hepatic deposition of TCDD was observed in all three mixed dose groups but TCDD did not influence hepatic HxCB deposition. TCDD did increase both CYP1A1 and CYP1A2 protein levels. In the HxCB-treated groups, CYP1A2 levels were also increased in a dose-dependent way but CYP1A1 levels were not increased. CYP1A2 activities (ACOH), but not protein levels, in the TCDD groups cotreated with HxCB were higher than those in the group treated with TCDD alone. CYP1A1-dependent EROD activity and CYPlA2-dependent ACOH activity were induced in all treated dose groups. It is concluded that the present results do not confirm a direct role of CYP1A2 induction in the increase of hepatic TCDD levels by HxCB cotreatment in the mixed HxCB/TCDD dose groups. However, in this aspect, the discrepancy between CYP1A2 activities and protein levels remains to be explained.

O-dealkylation of resorufin ethers as an indicator of hepatic cytochrome P-450 isoenzyme induction in the cotton rat (Sigmodon hispidus): A method for monitoring environmental contamination

O-dealkylation of resorufin ethers as an indicator of hepatic cytochrome P-450 isoenzyme induction in the cotton rat (Sigmodon hispidus): A method for monitoring environmental contamination

The 3-methylcholanthrene-mimetic effect of 4,4′-dichlorobiphenyl-treatment on phenacetin-induced hepatic glutathione depletion and liver microsomal phenacetin O-deethylation in rats

Both 4,4′-dichlorobiphenyl (4,4′-DCB) and 3-methylcholanthrene (3-MC) caused a substantial increase of phenacetin-induced hepatic glutathione (GSH) depletion, whereas phenobarbital (PB) had no effect, suggesting that 4,4′-DCB possesses cytochrome P-448 inducing activity. The O-deethylation of phenacetin by liver microsomes from control and PB- and 4,4′-DCB-treated rats showed biphasic Michaelis-Menten kinetics, in contrast to the monophasic course after pretreatment with 3-MC. Hepatic phenacetin levels indicated that in vivo interaction with only a high affinity site is involved in the O-deethylation of phenacetin. 4,4′-DCB and 3-MC caused marked increases in intrinsic clearance and extraction ratio of phenacetin, whereas control values were obtained after PB-treatment. Because of an absence of a spectral change at low phenacetin concentrations, it could not be demonstrated whether the observed differences in metabolism should be ascribed to a change in binding of phenacetin to cytochrome P-450. The results of this study indicate that after pretreatment with various enzyme inducers the phenacetin-induced hepatic GSH depletion strongly correlates with microsomal phenacetin O-deethylation. Further, these findings suggest a discrepancy between 4,4′-DCB and PB in cytochrome P-450 inducing activity, as 4,4′-DCB mimics 3-MC in the induction of phenacetin O-deethylase. The difference between 4,4′-DCB and PB is discussed in relation to the multiplicity and induction of cytochrome P-450 isoenzymes.