Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.1 (alcohol dehydrogenase)
 9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rats with hereditary hypothalamic diabetes insipidus, devoid of endogenous ADH, exhibited a prompt antidiuresis when injected subcutaneously or intraarterially with ovine prolactin. The antidiuresis was accompanied by a decrease in free water clearance and an increase in urine osmolality without a change in osmolal clearance or creatinine excretion. Measurement of PAH and insulin clearances indicated that prolactin had no effect on renal plasma flow or glomerular filtration rate. Prolactin injection caused a transient decrease in urinary sodium excretion, but proximal tubular sodium reabsorption, estimated by lissamine green transit time, was unaffected. The antidiuretic effect of prolactin could not be attributed to ADH contamination of the ovine prolactin preparation. Kidney cyclic AMP content was increased significantly 5 min after injection of prolactin. Thus, prolactin has an antidiuretic effect similar to that which occurs as a result of ADH action on the kidney and does not require either the release or the presence of ADH in order to cause the antidiuresis. Further, the impaired water excretion cannot be attributed to an increase in proximal tubular sodium reabsorption or to alteration of renal hemodynamics. It is suggested that prolactin has a direct ADH-like action on the kidney resulting in antidiuresis.
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PMID:Antidiuretic action of prolactin in the rat with diabetes insipidus. 19 85

No study has, to our knowledge, evaluated the acute effects of low immunosuppressive doses of cyclosporin (CsA) on renal function. To establish whether a relationship exists between the dosage of CsA and the onset of nephrotoxicity, 28 rats were studied by renal clearances before (control) and after i.v. administration of different doses of CsA: 3 mg/kg b.w. (group 1); 7 mg/kg b.w. (group 2); 11 mg/kg b.w. (group 3); 15 mg/kg b.w. (group 4). No change in renal function was observed between control and the post-CsA period in groups 1 and 2. GFR (inulin clearance) was decreased vs the control period in group 3 and group 4 (-22% and -37%, respectively, P less than 0.001); the difference between these two groups was statistically significant (P less than 0.01). Effective renal plasma flow (PAH clearance) was similarly decreased in groups 3 and 4 vs their control periods (-21% and -28%, respectively, P less than 0.001) due to the increase of total renal vascular resistance (+41% and +42%, respectively, P less than 0.001). Filtration fraction was significantly decreased by CsA in group 4 (P less than 0.01 vs the control period). PAH renal extraction, urinary volume, and sodium and potassium excretion were similar in all groups before and after CsA. PRA and ADH were significantly increased only in group 4 (P less than 0.01) vs the baseline values. A high and significant relationship was detected between CsA dosage and the decrease of GFR (r = 0.81, P less than 0.001) and RPF (r = 0.612, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Absence of acute nephrotoxicity with low doses of cyclosporin: experimental study in the rat. 210 87

1. A renally active substance can be extracted in detectable quantity from 150 g flash-frozen active but not from 150 g flash-frozen flaccid striped muscle. This substance is identical to the 18-monoacetate of D-aldosterone (18-MA) in R(F) value in three solvent systems and in biological activity.2. The renally active substance is secreted into the blood stream by active but not by flaccid muscles.3. Bilateral stimulation of decentralized sciatic nerves causes diuresis, natriuresis, a rise in the clearances of creatinine and PAH without change in heart or respiratory rates, in cats under chloralose anaesthesia. These changes can be matched by I.V. infusion of ADH, 0.3-0.45 m-u./kg.min.4. The urinary changes caused by sciatic stimulation are not prevented by transection of the spinal cord but are abolished by hypophysectomy.5. Hence, like 18-MA, the muscle substance liberates ADH from the neurohypophysis.
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PMID:The isolation of a substance very closely resembling the 18-monoacetate of D-aldosterone from the venous blood of activated muscle and from contracting muscle. 582 45

Upon birth, the liver acquires new functions as a result of the initiation of expression of key enzymes. One example is the initiation of gluconeogenesis which depends on the induced appearance of phosphoenolpyruvate carboxykinase (P-pyruvate-CK) at birth. To characterize other genes that undergo such regulation, a differential screening was performed on a cDNA library from well-differentiated hepatoma cells. The pattern of tissue-specific and developmental-specific expression was determined for seven genes. Three clones, out of which two encode for the known genes alcohol dehydrogenase class I (ADH) and phenylalanine 4-monooxygenase (PAH) and a new gene (clone 116-3), exhibited a pattern of expression similar to that of the P-pyruvate-CK gene, i.e. their expression was liver and kidney specific and induced in the liver upon birth. Determination of the sequence of clone 116-3 revealed that it belonged to the UDP-glucuronosyltransferases type 2 (UGT2) family and thus was named UGT2B-rH4. To examine whether expression of the various genes could be prematurely induced by hormones in the fetal liver, either high levels of cAMP or low levels of insulin were induced in utero. The results demonstrated that cAMP induced a marked expression only of the genes for P-pyruvate-CK and ADH but not of those for PAH or UGT2B-rH4, while insulin deficiency induced premature expression of all four genes. We suggest that a set of genes whose expression is specifically induced in the liver upon birth can be prematurely induced by the hormones in utero.
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PMID:Identification of differentially expressed genes during hepatocytes development and characterization of their prenatal hormonal induction. 902 81

(+/-)-7,8-Dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol), a proximate carcinogen derived from benzo[a]pyrene (BP) requires further metabolic activation to exert its carcinogenic effects. Two principal pathways have been implicated, and these involve either the formation of (+/-)-trans-7,8-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) catalyzed by P450 1A1/P450 1B1 (NADPH-dependent monoxygenases) or the formation of benzo[a]pyrene-7,8-dione (BP-7,8-dione) catalyzed by human aldo-keto reductases AKR1A1 and AKR1C1-AKR1C4 [NAD(P)(H)-dependent oxidoreductases]. The relative contributions of the two pathways to PAH activation are unknown. In this study, BP-7,8-diol metabolism was studied in human bronchoalveolar H358 cell extracts. Parental H358 cells do not constitutively express P450 1A1/P450 1B1 or AKRs but were manipulated by induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to express P450 1A1/P450 1B1 or by stable transfection to express AKR1A1 (aldehyde reductase). TCDD induction of AKR1A1 transfectants provided a cell line that expressed both pathways. Extracts derived from parental H358 cells plus TCDD (P450 induction) produced electrophilic anti-BPDE, which hydrolyzed to benzo[a]pyrene tetrahydrotetrols (BP-tetrols), extracts derived from AKR1A1-transfected cells (AKR1A1 expression) produced reactive and redox-active BP-7,8-dione, which was trapped in situ as its mono(thioether) conjugate, and extracts derived from AKR1A1 transfectants plus TCDD (coexpression of P450 1A1/P450 1B1 and AKR1A1) produced both anti-BPDE and BP-7,8-dione. The competing activation of BP-7,8-diol by P450 1A1/P450 1B1 and AKR1A1 was studied with varied NADPH:NAD+ ratios. The system with a relatively higher concentration of NADPH favored formation of anti-BPDE via P450 1A1/P450 1B1, while the system with the higher concentration of NAD+ favored formation of BP-7,8-dione via AKR1A1. Under conditions that mimic the cellular redox state, 10 microM NADPH and 1 mM NAD+, equal amounts of BP-tetrols and BP-7,8-dione were formed. This suggests that P450 1A1/P450 1B1 and AKR1A1 play competing roles in the metabolic activation of BP-7,8-diol and that the dominant pathway of BP-7,8-diol activation depends on the redox state of the cells. These model systems provide a cellular context in which the dominant DNA adducts/lesions formed by either pathway may be compared.
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PMID:Competing roles of cytochrome P450 1A1/1B1 and aldo-keto reductase 1A1 in the metabolic activation of (+/-)-7,8-dihydroxy-7,8-dihydro-benzo[a]pyrene in human bronchoalveolar cell extracts. 1572 Jan 44

Benzo[a]pyrene (BP) requires metabolic activation to electrophiles to exert its deleterious effects. We compared the respective roles of aldo-keto reductase 1A1 (AKR1A1, aldehyde reductase) and P4501B1 in the formation of BP-7,8-dione and BP-tetrols, respectively, in intact bronchoalveolar cells manipulated to express either enzyme. Metabolite formation was confirmed by HPLC/MS and quantitatively measured by HPLC/UV/beta-RAM. In TCDD-treated H358 cells (P4501B1 expression), the anti-BPDE hydrolysis product BP-tetrol-1 increased over 3-12 h to a constant level. In H358 AKR1A1 transfectants, formation of BP-7,8-dione was elevated for 3-12 h but significantly decreased after 24 h. Interestingly, BP-tetrols were also detected in AKR1A1 transfectants even though they do not constitutively express P4501A1/P4501B1 enzymes. Northern and Western blotting confirmed the induction of P4501B1 by BP-7,8-dione in parental cells and the induction of P4501B1 by BP-7,8-diol in AKR1A1-transfected cells. P4501B1 induction was blocked in AKR1A1 transfectants by the AKR1A1 inhibitor (sulfonylnitromethane), the o-quinone scavenger (N-acetyl-l-cysteine), or the cytosolic AhR antagonist (diflubenzuron). Attenuation of P4501B1 induction in these cells was verified by measuring a decrease in BP-tetrol formation. Our studies show that the formation of BP-7,8-dione by AKR1A1 in human bronchoalveolar cells leads to an induction of P4501B1 and that a functional consequence of this induction is elevated anti-BPDE production as detected by increased BP-tetrol formation. Therefore, the role of AKR1A1 in the activation of BP-7,8-diol is bifunctional; that is, it directly activates BP-7,8-diol to the reactive and redox-active PAH o-quinone (BP-7,8-dione) and it indirectly trans-activates the P4501B1 gene by generating the aryl hydrocarbon receptor (AhR) ligand BP-7,8-dione.
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PMID:Competing roles of aldo-keto reductase 1A1 and cytochrome P4501B1 in benzo[a]pyrene-7,8-diol activation in human bronchoalveolar H358 cells: role of AKRs in P4501B1 induction. 1641 58