Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is widely known that the clearance of drugs is often compromised during episodes of infectious disease via a down-regulation of cytochrome P450 (P450) at a pre-translational step in enzyme synthesis. Etiocholanolone (ETC), a potent inflammatory agent, induces fever in humans and causes a decrease in the clearance of certain drugs that are metabolized by P450. On this basis it is widely believed that the fever per se rather than the immune modulation that occurs during infections may have a major role in depression of microsomal P450 enzymes during viral infections in humans. In the present study, we demonstrated that although ETC did not induce hyperthermia in mice, it still evoked a depression of the levels of P450 in hepatic microsomes. Ethoxyresorufin O-deethylase (EROD) was also inhibited significantly when hepatic microsomes were incubated with various concentrations of ETC in vitro. P450 levels and EROD activities remained unchanged following hyperthermia that was induced by a non-inflammatory procedure using 2,4-dinitrophenol. Provided the response in rodents is similar to humans, these results indicate that the depression of drug biotransformation by ETC in humans is more likely to be caused by the direct effects of this agent or other mechanisms rather than by the fever it produces. This may suggest that the loss of drug metabolism in humans during infections is due to the activation of host defence responses rather than to the febrile nature of the illness.
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PMID:Modulatory effect of hyperthermia on hepatic microsomal cytochrome P450 in mice. 834 53

Major depression is a common, serious, and potentially life-threatening illness in the elderly. Moreover, this population is perhaps the most difficult to treat effectively and safely for this disease. Changes in physiology associated with advancing age produce clinically significant differences in drug metabolism and pharmacokinetics in these patients versus younger individuals. The elderly are also more likely than young patients to receive treatment for multiple illnesses. This fact increases the potential for serious pharmacodynamic and pharmacokinetic drug-drug interactions. The practicing clinician now has five distinct classes of antidepressant medications that may be used for treating depression in the elderly: tricyclic antidepressants (TCAs; e.g., desipramine, nortriptyline), monoamine oxidase inhibitors (MAOIs; e.g., isocarboxazid, tranylcypromine), selective serotonin reuptake inhibitors (SSRIs; i.e., fluoxetine, sertraline, and paroxetine), aminoketones (i.e., bupropion), and triazolopyridines (i.e., trazodone). Although all are effective antidepressants, the SSRI class may be the best choice for the treatment of elderly depressed patients, based on a number of considerations. SSRIs have a broad spectrum of antidepressant activity, being effective in different types of major depressive episodes (e.g., melancholic, atypical), have a wide therapeutic index, and are free of many potentially serious adverse effects associated with other antidepressants, such as central nervous system and cardiovascular toxicity (TCAs, bupropion), orthostatic hypotension (TCAs, MAOIs, and trazodone), and sedation (TCAs, trazodone). While SSRIs as a group share a common presumed mechanism of action, there are clinically important differences among the members of this class. First, the pharmacokinetics of sertraline are the same in both elderly and younger patients, whereas elderly, in comparison with younger, patients develop higher plasma levels of fluoxetine (and its active metabolite, norfluoxetine) or paroxetine, when given the same dose. Second, the SSRIs differ in their potential for pharmacokinetic interactions with other psychotropic and nonpsychotropic drugs. Fluoxetine, norfluoxetine (the major metabolite of fluoxetine), and paroxetine are potent inhibitors of the hepatic isoenzyme P450 IID6, whereas sertraline has much weaker inhibitory effects on its activity. Inhibition of P450 isoenzymes can cause potentially dangerous increases in the plasma levels of a large number of drugs, including TCAs, neuroleptics, and mood stabilizers, such as carbamazepine. Thus, sertraline has several characteristics that offer advantages over other members of this class of antidepressants for the treatment of the elderly patient with major depression.
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PMID:Recent pharmacologic advances in antidepressant therapy for the elderly. 850 77

Fluoxetine and other selective serotonin reuptake inhibitors (SSRIs) are effective for the treatment of depression in the elderly and offer a safer side-effect profile as compared to tricyclics and monoamine oxidase inhibitors. We report a case in which a patient treated with fluoxetine developed parkinsonism following the introduction of cimetidine. Inhibition of hepatic P450 cytochrome enzymes by cimetidine with an increase in serum levels of norfluoxetine may have precipitated this extrapyramidal syndrome, which has been related to agonism of the serotonergic input to nigrostriatal tracts and basal ganglia. Parkinsonism as a side effect of SSRIs occurs infrequently, suggesting an idiosyncratic response resulting from a functional imbalance of serotonergic and dopaminergic activity in susceptible individuals. Careful monitoring of geriatric patients treated with fluoxetine is indicated, particularly for those on high doses, those with impaired hepatic functioning, or those treated with concurrent medications that slow the metabolism of fluoxetine.
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PMID:Parkinsonism associated with fluoxetine and cimetidine: a case report. 856 37

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exhibits remarkably potent antiestrogenic activity. To further elucidate the role of estrogen receptor (ER) regulation in this response, we examined the effects of exposure to TCDD in MCF-7 human breast cancer cells on ER mRNA levels by using an RNase protection assay, on ER accumulation by using an ER immunocytochemical essay (ER-ICA), and on ER function by competitive binding assays under conditions of saturating 17 beta-estradiol (E2). Comparative studies were conducted with E2 and 12-O-tetradecanoylphorbol-13-acetate (TPA), as both compounds are known to suppress ER expression. Our results indicate that 1 nM E2 and 100 nM TPA both suppress ER mRNA levels as early as 4 h after exposure and to 33.6% and 16.5% of control levels, respectively, after 72 h. In contrast, no significant effect on ER mRNA levels was attributed to exposure to 10 nM TCDD. A greater than 50% reduction in positive staining was observed by ER-ICA after 72 h exposure to 1 nM E2 and to 100 nM TPA, while only an 11% reduction in positive staining was observed with 10 nM TCDD. Specific binding of [3H]E2 under saturating conditions (10 nM E2) in whole cells was reduced by 50% in cultures exposed to 100 nM TPA, although no effect on binding was observed with exposure to 10 nM TCDD. In contrast, specific binding using subsaturating 1 nM [3H]E2 was depressed by 49% in MCF-7 cells exposed to 10 nM TCDD for 72 h. This depression was inhibited by a 1-h treatment with 5 microM alpha-naphthoflavone, which inhibits TCDD-induced, P450-mediated, E2 metabolism, and subsequent E2 depletion. In conclusion, while TPA and E2 effectively down-regulate ER expression, TCDD, under antiestrogenic conditions, has little if any effect on total ER levels in MCF-7 cells, and thus ER modulation is probably not necessary for the suppression of estrogenic activity in MCF-7 cells by TCDD.
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PMID:Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin, 12-O-tetradecanoylphorbol-13-acetate and 17 beta-estradiol on estrogen receptor regulation in MCF-7 human breast cancer cells. 865 28

The expression of constitutive and inducible cytochrome P450s has been shown to be downregulated by interferon through an unknown pretranslational mechanism that depresses the mRNA encoding P450 apoproteins. To establish an association between gene transcription and P450 apoprotein downregulation by interferon, we studied the effect of recombinant interferon (IFN-alpha 2a) on CYP1A1 in human B lymphoblastoid cell lines. The cHoI cell line expresses inducible native CYP1A1, while the genetically engineered derivative h1A1 v2 expresses a noninducible extrachromosomal vector-derived human CYP1A1 cDNA lacking the CYP1A1 promoter region. We characterized CYP1A1 activity, apoprotein, and mRNA by ethoxyresorufin O-deethylase activity, Western immunoblotting, and Northern blot analysis, respectively. In cHoI cells, following induction with dibenz[a,h]anthracene, interferon depressed CYP1A1 apoprotein and mRNA levels by 55 and 76%, respectively, with no detectable changes in enzyme activity. In h1A1 v2, however, interferon increased CYP1A1 activity, apoprotein, and mRNA. The depression of CYP1A1 mRNA and apoprotein levels incHoI cells, in contrast with the increase observed in h1A1 v2 cells, suggests that nuclear mechanisms are essential for interferon-mediated depression of inducible P450s. From our preliminary results we propose that interferon-mediated downregulation of CYP1A1 may result from inhibition of gene transcription.
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PMID:Interferon-mediated changes in the expression of CYP1A1 in human B lymphoblastoid (AHH-1 TK +/-) cells. 883 82

It is now established that inflammatory stimuli such as lipopolysaccharides (LPS) and polyinosinic acid:polycytidylic (polyIC) suppress hepatic expression of cytochrome P450 (P450) genes in rat liver. Previous studies have suggested that LPS- or polyIC-induced downregulation of P450 was due to endogenously released inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1, interleukin-6, and interferons (IFNs). To improve our understanding of the role of inflammatory cytokines in mediating P450 depression, we investigated the possibility of preventing P450 downregulation with pentoxifylline. Pentoxifylline has been shown to inhibit LPS-induced TNF-alpha production by suppression of TNF-alpha gene expression. The present study shows that in uninduced male rats pentoxifylline selectively prevents the downregulation of microsomal P4501A2 and P4502B caused by LPS. No protective effect of pentoxifylline on the downregulation of P4502E1 and P4503A1/2 was observed. PolyIC-induced downregulation of P4501A2, P4502B, P4502E1, and P4503A1/2 was not affected by pentoxifylline. These results suggest that the LPS-induced downregulation of P4501A2 and P4502B is mediated to a large extent by TNF-alpha. Other cytokines might be involved in the suppression of P4502E1 and P4503A1/2. The fact that polyIC-induced downregulation is not protected by pentoxifylline is further evidence that this agent acts via a selective induction of IFNs.
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PMID:Differential effect of pentoxifylline on lipopolysaccharide-induced downregulation of cytochrome P450. 893 26

The influence of UVA and UVB irradiation of the skin for 1, 2 and 4 weeks on the activities of the hepatic and cutaneous P450 isoenzymes was investigated in female Wistar rats before and after systemic administration of hexachlorobenzene (HCB), a well-known porphyrogenic agent, which additionally induces P450 1A1 and P450 1A2 isoenzymes. UVA and UVB irradiation of the skin of controls and HCB-treated animals did not influence porphyrin metabolism. In the nonporphyric rats hepatic EROD (P450 1A1) activity was induced by UVB, but the activity of ADM (P450 2B) and EMDM (P450 3A) was either minimally or not affected. In the HCB-treated (porphyric) rats UVA and UVB irradiation resulted in a significant depression of HCB-induced EROD in the liver and in the skin. In both the nonporphyric and the porphyric rats UVA and UVB irradiation had no effect on hepatic ADM activity. In the liver of the nonporphyric animals EMDM activity remained unchanged after UVA and UVB irradiation, whereas in the HCB-treated animals the activity of this enzyme was increased. Finally, after UVA and UVB irradiation cutaneous EMDM activity was increased in the controls, whereas the HCB-induced increase of this enzyme in porphyric animals was decreased. In addition long-term (28 days) UVB irradiation decreased hepatic GSH content significantly in normal and porphyric rats. These experimental findings cannot be directly extrapolated to humans; however, they suggest that exposure of human skin to UV radiation may result in alterations in the activity of cutaneous hepatic and other extracutaneous P450 isoenzymes.
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PMID:Influence of UVA and UVB irradiation on hepatic and cutaneous P450 isoenzymes. 901 35

In three experiments, mice from lines selected for resistance (R) or susceptibility (S) to growth depression from endophyte-infected fescue seed in the diet were fed diets containing infected (E+) or non-infected (E-) seed. Activities of liver enzymes known to participate in oxidation, reduction, or hydrolysis or in conjugation of xenobiotics were measured in these mice. In all experiments, E+ caused greater reduction in initial ADG of S than of R mice. In Exp. 1, liver cytochromes P450 and b5 activities were not affected by line, diet, or their interaction. These enzymes were not evaluated in subsequent experiments. In all experiments, glutathione-S-transferase (GST) and uridine diphosphate glucuronosyltransferase (GRT) activities differed between lines. Resistant mice had significantly higher GST activity on both diets in Exp. 1, on E- in Exp. 2, and on E+ in Exp. 3. Resistant mice had higher GRT activities on E+ in Exp. 1, on E- in Exp. 2, but after 4 wk on either diet in Exp. 3. Before test diets were imposed in Exp. 3, GST and GRT activities were higher in R-line mice. Divergent selection created lines that differed in response to tall fescue in the diet. Postweaning growth of resistant mice was less severely depressed by E+, although susceptible mice later expressed compensatory gain. Activities of two detoxification enzymes generally were higher in livers from R-line mice, suggesting a biochemical mechanism for the difference. Using such traits, it may be possible to select ruminants for resistance to fescue toxicosis.
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PMID:Growth and physiological responses to toxicosis in lines of mice selected for resistance or susceptibility to endophyte-infected tall fescue in the diet. 926 65

There is increasing evidence suggesting that several mediators are involved in the cascade of events leading to the depression of the cytochrome P450 (P450) by an inflammatory reaction. The present study aimed to confirm the presence of mediators in the serum (RS(INFLA)) and hepatocytes (H(INFLA)) of rabbits with an acute inflammatory reaction, and in the serum of humans with an acute upper respiratory tract viral infection (HS(URTVI)). The inflammatory reaction was induced by the s.c. injection of 5 ml of turpentine. Incubation of RS(INFLA) or HS(URTVI) with H(INFLA) depressed the P450, diminished the formation of theophylline metabolites (3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid), and increased lipid peroxidation. The addition of preheated RS(INFLA) or HS(URTVI) to H(INFLA) did not diminish the amount of P450 or theophylline metabolites, and prevented the increase in lipid peroxidation. Incubating the filtrate of RS(INFLA) or HS(URTVI) dialyzed through membranes with cut-off of 10, 30, 50 and 100 kd, with H(INFLA) showed that rabbit and human mediators have molecular weights ranging from 10 to 30 kd. Incubation of H(INFLA) with hepatocytes from control rabbits (H(CONT)) did not decrease further the P450. However, when RS(INFLA) was added to co-cultured H(CONT) + H(INFLA), the depression of P450 was 37% greater (p<0.05), and the amount of theophylline metabolites generated was around 30% (p<0.05) smaller than that observed when H(CONT) or H(INFLA) were incubated with RS(INFLA). Based on the present results we may speculate that human and rabbit serum mediators are proteins of molecular weights ranging from 10 to 30 kd, and in addition, primed hepatocytes once exposed to the serum mediators release mediators able to depress the P450 in H(CONT).
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PMID:Depression of the hepatic cytochrome P450 by an acute inflammatory reaction: characterization of the nature of mediators in human and rabbit serum, and in the liver. 976 74

The renal tubular and hemodynamic effects of endothelin-1 (ET-1) were studied in the rat in terms of the participation of cytochrome P450 monooxygenases (CYP450)-derived arachidonic acid (AA) metabolites. The availability of specific mechanism-based inhibitors of CYP450-dependent AA metabolism has greatly facilitated studies designed to link AA metabolites generated by CYP450 to renal function. Eicosanoid products synthesized by cyclooxygenase (COX) and CYP450 can account for the renal functional effects of ET-1. Inhibition of COX decreased glomerular filtration rate (GFR) and potentiated the depression of GFR elicited by ET-1. In contrast, inhibition of CY-P450-dependent AA metabolism enhanced GFR and blunted ET-1 induced increase in renal vascular resistance, yet reduced the diuretic response to ET-1. Thus, CYP450-dependent AA products depress GFR and renal blood flow, while promoting sodium excretion. The effects of ET-1 on renal function correspond to those of 20-HETE, the predominant renal CYP450-derived AA metabolite.
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PMID:Renal functional effects of endothelins: dependency on cytochrome P450-derived arachidonate metabolites. 983 May 8


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