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Parameters for the binding of perazine (PER), amitriptyline (AT) and nortriptyline (NT) to plasma and to single plasma proteins were determined by equilibrium dialysis. The highest affinity (K at least 10 M) and lowest capacity (first site 1 mol/mol) towards all three drugs was exhibited by α-acid glycoprotein (α-AGP). From the parameters, α-AGP was estimated to contribute 43% to total binding of PER and 49 and 31%, respectively, to AT and NT binding in samples with normal protein concentrations. Fractions bound to total lipoproteins would amount to 32% (PER), 40% (AT) and 52% (NT), respectively, while the contribution of albumin would range from 11% (AT) to 25% (PER). The extent of the binding to plasma was compared with that to single proteins and their mixtures. Binding to combinations of α-AGP, lipoproteins and albumin exceeded that to plasma with PER, but not with AT and NT. This leads to the assumption that additional plasma constitutents interfere with PER binding. [ABSTRACT FROM AUTHOR]

The purpose of this study was to replicate the results of Pullarkat and Raguthu1 and Roine el al.2 who found elevated levels of urinary dolichol (long-chain 2,3-d-ihydropolyprenoIs) in chronic alcoholic patients. We investigated a sample of 21 alcohol-dependent inpatients voluntarily entering detoxification treatment. Urinary dolichol was only slightly increased as compared to 21 healthy controls. When dolichol was related to urinary creatinine no differences between alcoholic patients and controls could be found. Under conditions of confirmed abstinence the slightly elevated levels of dolichol returned to normal within 2 weeks. Compared with the sensitivity of γ-glutamyltranrferase which ranges from 72-85%, the value of urinary dolichol (sensitivity 9-19%) as a biochemical marker of alcoholism must be doubted. [ABSTRACT FROM AUTHOR]

Detoxication of the tobacco-specific carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in humans is mainly due to carbonyl reduction to the chiral alcohol 4-methylnitrosamino-1-(3-pyridyl)-1-butanol (NNAL), which undergoes glucuronidation and excretion. NNAL has a carcinogenic potential with (S)-NNAL being more tumorigenic in the mouse. Therefore, the enantioselectivity of NNK reductases seems toxicologically relevant. NNAL enantiomers were measured by a novel high-performance liquid chromatography procedure. The aldo-keto reductases AKR1C1, 1C2, and 1C4 and carbonyl reductase purified from human liver cytosol produced NNAL with >90% (S)-enantiomer in accordance with the enantioselectivity of NNK reduction by cytosol from liver, placenta, and lung. In contrast, the (R)-NNAL content was 35% on NNK reduction with 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) purified from human liver microsomes, but around 70% with human microsomes. The selectivity for (R)-NNAL formation was still higher with microsomes from placenta (87%) and lung (89% in 10 of 11 surgical samples). Microsomes from lung of one patient reduced NNK at a much lower rate, with production of 14% (R)-NNAL. This points to predominant reduction in microsomes by an enzyme with selectivity for (R)-NNAL formation that was apparently absent from the lung of one patient. Experiments with 18beta-glycyrrhetinic acid, a potent inhibitor of 11beta-HSD1, also indicated a minor or no role for 11beta-HSD1. Rat liver and lung microsomes produced NNAL with about 33% and 55% (R)-enantiomer and a mean contribution of 11beta-HSD1 of 12% and 32%, respectively. Multiple enzymes seem to participate in NNK reduction in human and rat tissues.