Renal cortical drug and xenobiotic metabolism following urinary tract obstruction

Renal cortical drug and xenobiotic metabolism following urinary tract obstruction. Renal cortical metabolism of drugs and xenobiotics was assessed with microsomes prepared from normal, contralateral and 4-day postobstructive hydronephrotic kidneys. Microsomal mixed-function oxidase and prostaglandin H synthase systems were determined in control and 3-methylcholanthrene-treated rabbits. Cytochrome P450 content and biphenyl-4-hydroxylase activity but not cytochromec reductase activity were reduced in the hydronephrotic kidney. 3-Methylcholanthrene treatment increased cytochrome P450 content and biphenyl-4-hydroxylase and acetanilide-4-hydroxylase activities in normal, contralateral, and hydronephrotic kidneys. However, even after 3-methylcholanthrene treatment, hydronephrotic kidney cytochrome P450 content and acetanilide-4-hydroxylase activity were not more than 20% of the corresponding normal kidney values. Prostaglandin H synthase metabolism of benzidine was observed in the hydronephrotic kidney but was at the limit of detection in normal or contralateral kidneys with or without 3-methylcholanthrene treatment. Characteristics of benzidine metabolism were consistent with the hydroperoxidase rather than the fatty acid cyclooxygenase activity of prostaglandin H synthase. Therefore, hydronephrosis alters the drug and xenobiotic metabolic profile of the renal cortex from a primarily mixed-function oxidase-dependent system to one with the potential for metabolism by the hydroperoxidase component of prostaglandin H synthase.Métabolisme cortical rénal des médicaments et xénobiotiques après obstruction du tractus urinaire. Le métabolisme cortical rénal de médicaments et de xénobiotiques a été étudié avec des microsomes préparés à partir des reins normaux, controlatérals, et hydronéphrotiques, 4 jours après une obstruction. Les systèmes microsomiaux de fonction oxydase mixte et de prostaglandine H synthétase ont été déterminés chez des lapins contrôles et traités par du 3-méthylcholanthrène. Le contenu en cytochrome P450 et l'activité biphényl-4-hydroxylase, mais non l'activité cytochromec réductase étaient diminués dans le rein hydronéphrotique. Le traitement par le 3-méthylcholanthrène a augmenté le contenu en cytochrome P450 et les activités biphényl-4-hydroxylase et acétanilide-4-hydroxylase chez les reins normaux, controlatérals et hydronéphrotiques. Cependant, même après traitement par le 3-méthylcholanthrène, le contenu en cytochrome P450 du rein hydronéphrotique et son activité acétanilide-4-hydroxylase n'étaient pas de plus de 20% des valeurs dans le rein normaux correspondant. Le métabolisme de la benzidine par la prostaglandine H synthétase était observable dans le rein hydronéphrotique, mais était à la limite de la détection dans les reins normaux ou controlatérals, avec ou sans traitement par le 3-méthylcholanthrène. Les caractéristiques du métabolisme de la benzidine étaient plus compatibles avec l'activité hydroperoxidase qu'avec l'activité cyclooxygénase des acides gras de la prostaglandine H synthétase. Ainsi, l'hydronéphrose altère le profil métabolique des drogues et des xénobiotiques dans le cortex rénal d'un système primitivement dépendant d'une fonction oxydase mixte à un système ayant la capacité de métabolisme par le constituant hydroperoxydase de la prostaglandine H synthétase

Cooxidation of benzidine by renal medullary prostaglandin cyclooxygenase

ABSTRAC

The Neurotoxicity of DOPAL: Behavioral and Stereological Evidence for Its Role in Parkinson Disease Pathogenesis

BACKGROUND: The etiology of Parkinson disease (PD) has yet to be fully elucidated. We examined the consequences of injections of 3,4-dihydroxyphenylacetaldehyde (DOPAL), a toxic metabolite of dopamine, into the substantia nigra of rats on motor behavior and neuronal survival. METHODS/PRINCIPAL FINDINGS: A total of 800 nl/rat of DOPAL (1 µg/200 nl) was injected stereotaxically into the substantia nigra over three sites while control animals received similar injections of phosphate buffered saline. Rotational behavior of these rats was analyzed, optical density of striatal tyrosine hydroxylase was calculated, and unbiased stereological counts of the substantia nigra were made. The rats showed significant rotational asymmetry ipsilateral to the lesion, supporting disruption of dopaminergic nigrostriatal projections. Such disruption was verified since the density of striatal tyrosine hydroxylase decreased significantly (p<0.001) on the side ipsilateral to the DOPAL injections when compared to the non-injected side. Stereological counts of neurons stained for Nissl in pars compacta of the substantia nigra significantly decreased (p<0.001) from control values, while counts of those in pars reticulata were unchanged after DOPAL injections. Counts of neurons immunostained for tyrosine hydroxylase also showed a significant (p=0.032) loss of dopaminergic neurons. In spite of significant loss of dopaminergic neurons, DOPAL injections did not induce significant glial reaction in the substantia nigra. CONCLUSIONS: The present study provides the first in vivo quantification of substantia nigra pars compacta neuronal loss after injection of the endogenous toxin DOPAL. The results demonstrate that injections of DOPAL selectively kills SN DA neurons, suggests loss of striatal DA terminals, spares non-dopaminergic neurons of the pars reticulata, and triggers a behavioral phenotype (rotational asymmetry) consistent with other PD animal models. This study supports the "catecholaldehyde hypothesis" as an important link for the etiology of sporadic PD