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)

One of the serious toxicities of cyclophosphamide chemotherapy is urotoxicity. In addition to causing leukopenia, high-dose cyclophosphamide caused both depression of hepatic microsomal enzyme activities and extensive urinary bladder damage, suggesting that a common biochemical mechanism may be responsible for both of these effects. Administration of 180 or 200 mg cyclophosphamide per kg to Wistar rats caused 41 to 67% decrease in aryl hydrocarbon hydroxylase activity, a 21 to 54% decrease in aminopyrine demethylase activity, and a 34 to 40% decrease in cytochrome P-450 content. This dose of cyclophosphamide also caused hematuria as well as necrosis and edema in the urinary bladder. Administration of N-acetylcysteine or sodium-2-mercaptoethane sulfonate (mesnum) with cyclophosphamide, while not protecting against leukopenia, protected against the enzymatic inactivation and urotoxicity. The biochemical basis of these observations is discussed. The results suggest that a common metabolite of cyclophosphamide, most probably acrolein, is responsible for both of these undesirable effects of cyclophosphamide therapy. Use of combinations including cyclophosphamide and an appropriate thiol may increase the therapeutic index of this drug.
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PMID:Protective role of thiols in cyclophosphamide-induced urotoxicity and depression of hepatic drug metabolism. 680 12

A single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7-tribromodibenzo-p-dioxin (2,3,7-TBDD), 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin (1,2,3,7,8,9-HCDD), 1,2,4,6,7,9-hexachlorodibenzo-p-dioxin (1,2,4,6,7,9-HCDD), or 1,3,6,8-tetrachlorodibenzo-p-dioxin (1,3,6,8-TCDD) was given to male rats (25 micrograms/kg, p.o.) and plasma concentration and biliary excretion of ouabain assessed 10 days later. Treatment of TCDD, 2,3,7-TBDD and to a lesser extent 1,2,3,7,8,9-HCDD increased the plasma concentration of ouabain and decreased its excretion into ouabain. TCDD, 2,3,7-TBDD and to a lesser extent, 1,2,3,7,8,9-HCDD decreased the bile flow. Liver wet weight was increased in TCDD and 2,3,7-TBDD treated rats. The magnitude of depression in ouabain excretion by those compounds was closely related to the reported relative binding affinity of the compound to liver cytosol and their induction potency of aryl hydrocarbon hydroxylase activity.
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PMID:Effects of halogenated dibenzo-p-dioxins on plasma disappearance and biliary excretion of ouabain in rats. 682 49

In order to assess the process of oxidation and conjugation involved in biotransformation of vinyl chloride (VC), rats were exposed to 50, 200, 500, 1000 and 20,000 ppm inhaled VC. The rate of urinary excretion of thiodiglycollic acid (TDGA) after exposure to each investigated concentration of VC depends on the activity of microsomal monooxygenase. In general, higher levels of TDGA in urine were reflected by a more significant depression of non-protein sulfhydryl content in the liver of rats, whereas no changes were observed in those with inhibited activity of microsomal monooxygenase and depressed urinary levels of TDGA. The significance of alcohol dehydrogenase in the metabolism of low concentrations of VC has not been confirmed. Metabolism of VC in the range of 50--2 000 ppm is mediated by microsomal monooxygenase followed by conjugation with thiols.
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PMID:Urinary excretion of thiodiglycollic acid and hepatic content of free thiols in rats at different levels of exposure to vinyl chloride. 700 10

The Ah locus represents a complex "cluster" of genese controlling the induction of numerous drug-metabolizing enzyme "activities" by polycyclic aromatic compounds. Allelic differences at the Ah locus are reflected in the large differences in inducibility of cytochrome P1-450 and benzo[a]pyrene metabolism in numerous tissues when the mice receive the chemical daily in their diet. This experimental model system offers to the hematologist and clinical pharmacologist a means to study genetic differences in toxic chemical depression of the bone marrow, as well as a potential model to study aplastic anemia and leukemia explainable on a single-gene basis. The genetically "responsive" individual who is at increased risk for cancer caused by subcutaneous or topical or intratracheal polycyclic hydrocarbons is at decreased risk for toxicity of the bone marrow and leukemia caused by oral benzo[a]pyrene (when compared with the genetically "nonresponsive" individual receiving the same dose of the same xenobiotic). In other words, tissue sites in direct contact with the carcinogen develop cancer in responsive animals because of induced P1-450; tissues in distant sites of the body may develop malignancy in nonresponsive animals because more carcinogen reaches that tissue due to decreased P1-450 induction all over the body and therefore decreased detoxication. Not only the dct with the carcinogen develop cancer in responsive animals because of induced P1-450; tissues in distant sites of the body may develop malignancy in nonresponsive animals because more carcinogen reaches that tissue due to decreased P1-450 induction all over the body and therefore decreased detoxication. Not only the dct with the carcinogen develop cancer in responsive animals because of induced P1-450; tissues in distant sites of the body may develop malignancy in nonresponsive animals because more carcinogen reaches that tissue due to decreased P1-450 induction all over the body and therefore decreased detoxication. Not only the dose but the route of administration and the tissue in which the malignancy or toxicity develops are therefore very important in the interpretation of data from tumorigenesis or toxicity experiments involving P1-450 inducers such as polycyclic hydrocarbons. There exists sufficient evidence that heritable variation of the Ah locus occurs in man. Growing evidence indicates that persons with higher aryl hydrocarbon hydroxylase inducibility in their cultured mitogen-activated lymphocytes may have a statistically significantly increased risk for certain types of cancer and drug toxicity. It remains to be determined at the present time, however, whether this genotype can be used as a biochemical marker in the individual patient for predicting increased susceptibility to certain types of environmentally caused cancers or toxicity in man.
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PMID:Genetic differences in susceptibility to chemically induced myelotoxicity and leukemia. 701 19

Early exposure to benzo(a)pyrene, B(a(P, produces long-lasting effects on the cytochrome P-450 dependent monooxygenase system of rat liver microsomes. Adult male offspring of rats given B(a(P, 20 mg/kg i.p. during late pregnancy, showed either a small but significant depression of basal aryl hydrocarbon hydroxylase acitivity or an impaired induction response to B(a)P. Few significant changes were found in the relative amounts of the individual metabolites formed from B(a)P by microsomes from perinatally exposed rats, either in the basal or B(a)P-induced state. In addition, perinatal exposure to B(a)P tended to decrease the binding of B(a)P to calf thymus DNA in in vitro incubations.
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PMID:Effects of perinatal exposure to benzo(a)pyrene on the aryl hydrocarbon hydroxylase system of adult rat liver. 741 8

Aflatoxins are suspected human carcinogens and are also known to possess diverse toxicological activities. In the present communication an attempt has been made to evaluate the effects of aflatoxin B1 (AFB1) on hepatic microsomal drug metabolizing enzymes in growing rats. The weanling rats were exposed to 60, 300 or 600 micrograms AFB1/kg body weight, per os, on alternate days for 4 weeks, in 0.2 ml corn oil. A significant depression in the activities of aryl hydrocarbon hydroxylase (AHH), aniline hydroxylase (AH) and aminopyrene-N-demethylase (AND) was observed at 300 micrograms and 600 micrograms doses of AFB1. However, no significant change was recorded in glutathione-S-transferase (GST) activity and total sulphydryl (SH) content upon AFB1 exposure in weanling rats. Thus, AFB1 appears to have more pronounced effect on the phase I, rather than phase II, biotransformation enzyme system in weanling rats. The depression of drug metabolizing enzymes together with suppression of immunity by AFB1, as reported earlier by us, may increase the susceptibility of the host to toxic chemicals, drugs and infectious agents, particularly during the post-natal period.
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PMID:Aflatoxin induces depletion of activities of phase I biotransformation enzymes in growing rats. 800 97

Acute intraperitoneal administration of benzo(a)pyrene (80 mg/kg b.wt.) resulted in time-dependent increases in chromosome aberrations, especially of break-type in the bone marrow of treated mice. Pretreatment with murine interferon-alpha/beta (5 x 10(4) IU daily for two days) caused a significative decrease in the cytogenetic response in vivo of benzo(a)pyrene (up to 51%) and a stabilization of aberrant cells up to 48 hr. The administration of murine interferon-alpha/beta gave rise to a marked depression of microsomal monooxygenase system after 24 hr, as exemplified by the significant reduction of cytochrome P450 content as well as deethylation of ethoxyresorufin. Interferon treatment delayed the obtainment of basal levels of oxidative metabolism to approximately 30 hr. After interferon plus benzo(a)pyrene treatment, ethoxyresorufin O-deethylase activity showed a reduction up to 60%; levels comparable to benzo(a)pyrene treated group were restored by 48 hr. Immunoblotting analysis confirmed reduced CYP1A1 level. Results suggest that the inhibition of benzo(a)pyrene hepatic metabolism by interferon was reflected by changes in its clastogenic activity. Persistence of low level of chromosome aberration at 48 hr may be reconducible to other interferon sensitive processes than effects on hepatic mixed-function oxidase system, such as DNA repair activity and cell proliferation.
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PMID:The modulating activity of interferon on benzo(a)pyrene bioactivation and clastogenesis in mice. 809 Jun 95

A 24-h pretreatment of mice with diphtheria and tetanus toxoids and whole-cell pertussis vaccines depressed liver cytochrome P-450 and therefore prolonged hexobarbital-induced sleeping time in mice. The depression of liver drug metabolism by a cellular vaccine containing a mutated pertussis toxin was less marked than that induced by the wild-type vaccines, indicating that the mutated vaccine might have lower toxicity in this regard. The wild-type vaccines decreased microsomal P-450 levels by 50%, while the mutated whole-cell vaccine had a less marked effect (a decrease of 30%), paralleling the results obtained in sleeping time experiments. Furthermore, an acellular mutated vaccine did not affect liver drug metabolism, indicating a role of the whole bacterial cell in this side effect. All the cellular vaccines studied induced high serum interleukin-6 levels; on the other hand, the acellular mutated vaccine induced very low interleukin-6 levels, indicating that the whole bacterial cell is also important for interleukin-6 induction. All vaccines studied were very poor tumor necrosis factor inducers.
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PMID:Depression of liver metabolism and induction of cytokine release by diphtheria and tetanus toxoids and pertussis vaccines: role of Bordetella pertussis cells in toxicity. 826 41


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