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)

1,1-Dichloroethane (DCE) is a solvent that is often found as a contaminant of drinking water and a pollutant at hazardous waste sites. Information on its short- and long-term toxicity is so limited that the U.S. EPA and ATSDR have not established oral reference doses or minimal risk levels for the volatile organic chemical (VOC). The acute oral LD(50) in male Sprague-Dawley (S-D) rats was estimated in the present study to be 8.2 g/kg of body weight (bw). Deaths appeared to be due to CNS depression and respiratory failure. In an acute/subacute experiment, male S-D rats were given 0, 1, 2, 4, or 8 g DCE/kg in corn oil by gavage for 1, 5, or 10 consecutive days. The animals were housed in metabolism cages for collection of urine and sacrificed for blood and tissue sampling 24 h after their last dose. There were decreases in body weight gain and relative liver weight at all dosage levels, as well as increased renal nonprotein sulfhydryl levels at 2 and 4 g/kg after 5 and 10 days. Elevated serum enzyme levels, histopathological changes, and abnormal urinalyses were not manifest. For the subchronic study, adult male S-D rats were gavaged with 0.5, 1, 2, or 4 g DCE/kg 5 times weekly for up to 13 weeks. Animals receiving 4 g/kg exhibited pronounced CNS depression, with more than one-half dying by week 11. The 2-g/kg rats exhibited moderate CNS depression. One 2-g/kg rat died during week 6. There were very few manifestations of organ damage in animals that succumbed or in survivors at any dosage level. Decreases in bw gain and transient increases in enzymuria were noted at 2 and 4 g/kg. Serum enzyme levels and blood urea nitrogen were not elevated, nor were glycosuria or proteinuria present. Chemically induced histological changes were not seen in the liver, kidney, lung, brain, adrenal, spleen, stomach, epididymis, or testis. Hepatic microsomal cytochrome P450 experiments revealed that single, high oral doses of DCE did not alter total P450 levels, but did induce CYP2E1 levels and activity and inhibit CYP1A1 activity. These effects were reversible and regressed with repeated DCE exposure. There was no apparent progression of organ damage during the 13-week subchronic study, nor appearance of adverse effects not seen in the short-term exposures. One g/kg orally (po) was found to be the acute, subacute, and subchronic LOAEL for DCE, under the conditions of this investigation. In each instance, 0.5 g/kg was the NOAEL.
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PMID:Acute, subacute, and subchronic oral toxicity studies of 1,1-dichloroethane in rats: application to risk evaluation. 1160 9

Capsaicin is a common dietary constituent and a popular homeopathic treatment for chronic pain. Exposure to capsaicin has been shown to cause various dose-dependent acute physiological responses including the sensation of burning and pain, respiratory depression, and death. In this study, the P450-dependent metabolism of capsaicin by recombinant P450 enzymes and hepatic and lung microsomes from various species, including humans, was determined. A combination of LC/MS, LC/MS/MS, and LC/NMR was used to identify several metabolites of capsaicin that were generated by aromatic (M5 and M7) and alkyl hydroxylation (M2 and M3), O-demethylation (M6), N- (M9) and alkyl dehydrogenation (M1 and M4), and an additional ring oxygenation of M9 (M8). Dehydrogenation of capsaicin was a novel metabolic pathway and produced unique macrocyclic, diene, and imide metabolites. Metabolism of capsaicin by microsomes was inhibited by the nonselective P450 inhibitor 1-aminobenzotriazole (1-ABT). Metabolism was catalyzed by CYP1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Addition of GSH (2 mM) to microsomal incubations stimulated the metabolism of capsaicin and trapped several reactive electrophilic intermediates as their GSH adducts. These results suggested that reactive intermediates, which inactivated certain P450 enzymes, were produced during catalytic turnover. Comparison of the rate and types of metabolites produced from capsaicin and its analogue, nonivamide, demonstrated similar pathways in the P450-dependent metabolism of these two capsaicinoids. However, production of the dehydrogenated (M4), macrocyclic (M1), and omega-1-hydroxylated (M3) metabolites was not observed for nonivamide. These differences may be reflective of the mechanism of formation of these metabolites of capsaicin. The role of metabolism in the cytotoxicity of capsaicin and nonivamide was also assessed in cultured lung and liver cells. Lung cells were markedly more sensitive to cytotoxicity by capsaicin and nonivamide. Cytotoxicity was enhanced 5 and 40% for both compounds by 1-ABT in BEAS-2B and HepG2, respectively. These data suggested that metabolism of capsaicinoids by P450 in cells represented a detoxification mechanism (in contrast to bioactivation).
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PMID:Metabolism of capsaicin by cytochrome P450 produces novel dehydrogenated metabolites and decreases cytotoxicity to lung and liver cells. 1264 34

Polyhalogenated compounds, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, are associated with toxic Uroporphyria and cause alleviation of jaundice in the Gunn rat. These effects have been attributed to a microsomal oxidation of uroporphyrinogen and bilirubin for which supportive evidence has been obtained in vitro. CYP1A1 required planar polyhalogenated biphenyls for these oxidative reactions, while CYP1A2 was capable of oxidation in their absence. We have now used rat CYP1A1 and confirmed with the pure enzyme that increased bilirubin oxidation was caused by the addition of 3,4,3',4'-tetrachlorobiphenyl. CYP1A2 was more active than CYP1A1 at oxidizing bilirubin in presence of NADPH alone and reacted to addition of 3,4,3',4'-tetrachlorobiphenyl with a depression rather than a stimulation of bilirubin oxidation. We have also tested a bacterial enzyme, CYP102. Dodecanoic acid and its polyhalogenated analogue (perfluorododecanoic acid) both stimulated NADPH oxidation by CYP102, but only the perfluoro analogue stimulated markedly bilirubin oxidation. The analogue exhibited much greater potency than the normal substrate in stimulating NADPH and bilirubin oxidation and also showed greater affinity for CYP102, as measured by the binding constant, Ks. The molar stoichiometry ratio between NADPH and O(2) consumption was 1 in the case of the substrate, but approximated 2 with the perfluoro analogue. We conclude that halogenated substrate analogues can interact with different CYPs to increase production of oxidative species, probably by an uncoupling mechanism. A role of the ferryl-oxygen intermediate is suggested in the oxidation of biologically important molecules, with possible implications for the therapy of jaundice and for toxic oxidative reactions, such as uroporphyria and cancer.
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PMID:Interaction of polyhalogenated compounds of appropriate configuration with mammalian or bacterial CYP enzymes. Increased bilirubin and uroporphyrinogen oxidation in vitro. 1290 39

The cytochrome P450 (CYP1A1) enzyme metabolically activates many polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), to DNA- and protein-binding intermediates that are associated with toxicity, mutagenesis, and carcinogenesis. As a result, it is widely accepted that CYP1A1 potentiates the toxicity of this class of chemicals. In distinct contrast, we show here that CYP1A1 inducibility is essential in the detoxication of oral BaP. We compared Cyp1a1(-/-) knockout mice, having the genetic absence of the CYP1A1 enzyme, with Cyp1a1(+/+) wild-type mice. At an oral BaP dose of 125 mg/kg/day, Cyp1a1(-/-) mice died within 30 days whereas Cyp1a1(+/+) mice displayed no outward signs of toxicity. The rate of BaP clearance was 4-fold slower in Cyp1a1(-/-) than Cyp1a1(+/+) mice. The cause of death in Cyp1a1(-/-) mice receiving oral BaP seemed to be immunotoxicity, including toxic chemical depression of the bone marrow; some toxic effects in Cyp1a1(-/-) mice were noted at a BaP dose as low as 1.25 mg/kg/day. DNA post-labeling studies demonstrated dramatically higher BaP-DNA adduct levels in all Cyp1a1(-/-) tissues assayed, with the exception of the small intestine, which is probably a major site of BaP metabolism in Cyp1a1(+/+) mice. Different BaP-DNA adduct patterns were also observed between the two genotypes receiving oral BaP. Despite previous studies in vitro and in cell culture that have shown a participatory role for CYP1A1 in BaP toxicity, the present data indicate that, in the intact animal, inducible CYP1A1 is extremely important in detoxication and protection against oral BaP toxicity.
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PMID:Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation. 1510 51

A body of evidence suggests that pregnancy may be responsible for the depression in the microsomal enzyme activity and the reduction in the total content of cytochrome P450 (CYP) in the rat liver. However, changes in expression of individual CYP isozyme remain poorly known. The current study was designed to examine the changes in CYPs protein expression in the liver of F344 rats in midpregnancy and late pregnancy by Western blot analysis and immunohistochemistry. Total nine antirat CYPs antibodies (CYP1A1, CYP2B1/CYP2B2, CYP2C6, CYP2C12, CYP2D1, CYP2D4, CYP2E1, CYP3A1, and CYP4A1) were used. In comparison with age-matched nonpregnant control rats, there were significant decreases in hepatic levels of CYP2B2, CYP2C6, and CYP4A1 in midpregnancy (day 13) and CYP2B2, CYP2C6, CYP4A1, CYP1A1, CYP2B1, and CYP2E1 in late pregnancy (day 19). The expression of CYP2C12, CYP2D1, and CYP 3A1 did not differ between nonpregnant and pregnant rats, and CYP2D4 was not detectable in microsomal proteins obtained from nonpregnant and pregnant rats at a protein loading of 20 mug total protein per lane. Immunohistochemistry showed that there were no differences in the distribution and degree of immunostainability for the abovementioned antibodies to nine CYPs between pregnant and nonpregnant rats.
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PMID:Effects of pregnancy on CYPs protein expression in rat liver. 1559 63

Single nucleotide polymorphism (SNP) genotype frequencies were examined to determine whether variation in 6 estrogen-related genes was associated with differences in self-reported depressive symptoms in women. In this substudy of the Study of Women's Health Across the Nation (SWAN), DNA from a multiracial/multiethnic sample of 1,538 African American, Caucasian, Chinese, and Japanese women aged 42 to 52 years participating in SWAN was genotyped. Depressive symptoms were measured with the Center for Epidemiologic Studies-Depression (CES-D) scale. After excluding data from women taking antidepressants (n=103), statistical models were fit using multivariate logistic regression to predict the association of estrogen-related polymorphisms with the dichotomized CES-D score. Among Caucasian women, those with the CYP1A1 rs2606345 CC and AC genotypes had approximately 2-fold greater odds of having depressive symptoms than did those with the AA genotype (95% confidence intervals [CIs], 1.33 to 4.66 and 1.25 to 3.14, respectively). African American women with the CC genotype of the same SNP had 10-fold greater odds of having more depressive symptoms than did women with the AA genotype (95% CI, 1.20 to 86.20). In Japanese women, the odds of depressive symptoms were nearly 5-fold higher among those with CYP 19 rs936306 TT genotype (95% CI, 1.10 to 22.17) than in women with the CC genotype and 9.6-fold higher (95% CI, 2.01 to 45.81) than in women with the CT genotype. The odds of depressive symptoms among Chinese women with the 17HSD rs615942 TT genotype were nearly 11-fold higher than in those with the GT genotype (95% CI, 1.94 to 60.84) and >7-fold higher than in those with the GG genotype (95% CI, 1.13 to 51.82). These data provide evidence that selected genes involved in estrogen synthesis and metabolism increase the odds of more depressive symptoms in women who are premenopausal or perimenopausal.
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PMID:Sex steroid hormone gene polymorphisms and depressive symptoms in women at midlife. 1694 93

The Flinders Sensitive Line (FSL) rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed patients and has been very effective in screening antidepressants. Major factor that determines the effectiveness and toxicity of a drug is the drug metabolizing capacity of the liver. Therefore, in order to discriminate possible differentiation in the hepatic drug metabolism between FSL rats and Sprague-Dawley (SD) controls, their hepatic metabolic profile was investigated in this study. The data showed decreased glutathione (GSH) content and glutathione S-transferase (GST) activity and lower expression of certain major CYP enzymes, including the CYP2B1, CYP2C11 and CYP2D1 in FSL rats compared to SD controls. In contrast, p-nitrophenol hydroxylase (PNP), 7-ethoxyresorufin-O-dealkylase (EROD) and 16alpha-testosterone hydroxylase activities were higher in FSL rats. Interestingly, the wide spread environmental pollutant benzo(alpha)pyrene (B(alpha)P) induced CYP1A1, CYP1A2, CYP2B1/2 and ALDH3c at a lesser extend in FSL than in SD rats, whereas the antidepressant mirtazapine (MIRT) up-regulated CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2, mainly, in FSL rats. The drug also further increased ALDH3c whereas suppressed GSH content in B(alpha)P-exposed FSL rats. In conclusion, several key enzymes of the hepatic biotransformation machinery are differentially expressed in FSL than in SD rats, a condition that may influence the outcome of drug therapy. The MIRT-induced up-regulation of several drug-metabolizing enzymes indicates the critical role of antidepressant treatment that should be always taken into account in the designing of treatment and interpretation of insufficient pharmacotherapy or drug toxicity.
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PMID:Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression. 2059 28

Depression is a common mental illness, which is caused by 'liver qi stagnationin in traditional Chinese medicine (TCM) theory. Thus, relieving "liver qi stagnation" is considered to be effective at treating depression. The Radix Bupleuri and Radix Paeoniae Alba drug pair is the most classic compatible drug pair for mitigating a great variety of depression symptoms. However, its mechanisms remain largely unclear. In this study, metabolomics and network pharmacology methods were used to explore the potential mechanism of antidepressant-like effects of the Radix Bupleuri and Radix Paeoniae Alba drug pair. Analysis of metabolomics results showed that the drug pair can significantly improve CUMS-induced depression. The underlying mechanism of its antidepressant effect involves regulating the expression of brain-derived neurotrophic factors, inhibiting neurotoxicity, and regulating the HPA axis. Network pharmacology showed that drug pairs screened a total of 23 active ingredients and 63 targets, participated in the regulation of protein metabolism, Metabolism, Energy pathways, Cell growth and / or maintenance and other biological processes (BP), and mainly involved multiple signaling pathways and metabolic pathways to jointly exert antidepressant effects. Four related metabolic pathways regulated by the Radix Bupleuri and Radix Paeoniae Alba drug pair were input into the KEGG database to obtain the key genes of the related metabolic pathways. The predicted target of the network pharmacology was compared with the key genes of the metabolic pathway, and the common genes were screened: CYP1A1, CYP1A2; Western blot results showed that the drug pair up-regulated the protein expression of CYP1A1, CYP1A2. The medicine has an antidepressant effect by regulating the action of key enzymes. Metabolomics combined with network pharmacology research strategy revealed that antidepressant-like effects of the Radix Bupleuri and Radix Paeoniae Alba drug pair are characterized by multi-component, multi-target and multi-path mechanism of action.
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PMID:An integrative metabolomics and network pharmacology method for exploring the effect and mechanism of Radix Bupleuri and Radix Paeoniae Alba on anti-depression. 3265 15


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