INVOLVEMENT OF FASE I DRUG METABOLIZING SYSTEM IN THE METABOLIZATION OF PORPHYRINOGENIC AGENTS IN BRAIN. A COMPARATIVE STUDY IN LIVER AND KIDNEY

Jimena Lavandera, Alcira Batlle & Ana Maria Buzaleh

 

Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP) - CONICET and University of Buenos Aires. Argentina

 

 

The presence of the monooxygenase enzymes in brain, suggests that they have more specialized functions than the hepatic enzymes which participate in xenobiotic detoxification. Brain cytochrome P-450 (CYP) levels are only  4-10% of the corresponding hepatic content. CYP is mainly localized in mitochondria although a small quantity was found in the microsomal fraction.

The aim of this work was to evaluate the involvement of mitochondrial and microsomal mice brain CYP  in the metabolization of known porphyrinogenic agents and to compare their response in liver and kidney.

Some of the porphyrinogenic agents studied altered mitochondrial brain CYP but not the microsomal CYP. Thus, Gris induced a 70% (p<0.05) and chronic anaesthesia with Isoflurane produced a 30% (p<0.01) reduction. Instead, AIA diminished both microsomal and mitochondrial brain CYP content.

Hepatic CYP levels were altered in the most of the groups studied, in some cases a similar pattern was detected for the mitochondrial and microsomal CYP. However, after chronic Isoflurane administration, a 36% (p<0.05) diminution was only detected in the mitochondrial fraction.

Kidney CYP levels were only modified after Veronal administration and this effect was only observed in mitochondria.

Moreover, taking into account that ALA could be responsible for the neurological symptoms of acute porphyrias, the effect of this metabolite on tissues CYP levels was investigated. CYP reductase activity was also evaluated in all groups.

Our findings showed differential tissue response to the different xenobiotics assayed. Although the liver is the main tissue involved in the metabolization of exogenous drugs, extrahepatic tissues  can also participate. Brain CYP was more affected than kidney CYP and in all cases mitochondrial CYP was mainly involved.

The alterations provoked on brain CYP levels could be attributed to a direct effect on the Fase I drug metabolization system or indirectly, due to changes in the activities and expression of ALA-S and Heme oxygenase produced by some porphyrinogenic agents, as we have previously reported.