Involvement of phase I drug metabolizing system in the metabolization of porphyrinogenic agents in brain. A comparative study in liver and kidney

LAVANDERA, JIMENA; BATLLE, ALCIRA; BUZALEH, ANA MARIA

Ciudad del Cabo, Sudafrica

Congreso; Porphyrins and Porphyrias - Cape Town 2005; 2005

Universidad de Cape Town

The presence of the monooxygenase enzymes in brain, suggests that they have more specialized functions than the hepatic enzymes which participates in xenobiótico 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<0.05). 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 reductasa activity was also evaluated in all groups.   Our findings showed differential tissues responses 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 Phase I drug metabolization system or indirectly, due to changes in the activities and the expression of ALA-S and Heme oxygenase produced by some of porphyrinogenic agents, as we have previously reported