Purification and characterization of akr1b10 from human liver: role in carbonyl reduction of xenobiotics.

Members of the aldo-keto reductase (AKR) superfamily have a broad substrate specificity in catalyzing the reduction of carbonyl group-containing xenobiotics. In the present investigation, a member of the aldose reductase subfamily, AKR1B10, was purified from human liver cytosol. This is the first time AKR1B10 has been purified in its native form.

Carbonyl reduction of naltrexone and dolasetron by oxidoreductases isolated from human liver cytosol.

The opioid receptor antagonist naltrexone and the antiemetic 5-HT(3) receptor antagonist dolasetron are ketonic drugs that are efficiently reduced to their corresponding alcohols in-vivo. These experiments aimed at characterizing the role in these reactions of individual oxidoreductases present in human liver cytosol. Aldo-keto reductases (AKRs) and carbonyl reductase (CR, EC 1.

The metabolic fate of amitriptyline, nortriptyline and amitriptylinoxide in man.

Amitriptyline (AT), the most widely used tricyclic antidepressant, undergoes oxidative metabolism in the side chain with production of the secondary amine nortriptyline (NT), a primary amine, and the N-oxide amitriptylinoxide (AT-NO); in addition, direct conjugation leads to a quaternary ammonium-linked glucuronide. Hydroxylation of AT or NT at the ethylene bridge of the central seven-membered ring results in four isomeric alcohols and occurs with high stereo- and enantioselectivity, the (-)-(E)-10-hydroxy compounds usually being the major products. The disposition of the alcohols is also partially enantioselective, for instance with regard to glucuronidation and reversible oxidation to ketones.

Enantioselectivity of carbonyl reduction of 4-methylnitrosamino-1-(3-pyridyl)-1-butanone by tissue fractions from human and rat and by enzymes isolated from human liver.

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.

Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine.

In experiments with expressed human UDP-glucuronosyltransferase 1A4 (UGT1A4), the antipsychotic clozapine proved to be conjugated to two different glucuronides, one of which was identified as the quaternary ammonium glucuronide derivatized at the N-methylpiperazine group; this compound had previously been isolated from patient urine. An additional glucuronide produced in larger quantity was assumed to be conjugated at the secondary nitrogen of the central ring to form 5-N-glucuronide, but this was not proven. The analogous olanzapine 10-N-glucuronide was found to make a major contribution to urinary metabolites in human volunteers.