INVESTIGADORES
BUZALEH Ana Maria
artículos
Título:
Metabolization of porphyrinogenic agents in brain: involvement of the Phase I drug metabolizing system. A comparative study in liver and kidney
Autor/es:
LAVANDERA JIMENA; BATLLE, ALCIRA; BUZALEH ANA MARIA
Revista:
CELLULAR AND MOLECULAR NEUROBIOLOGY.
Editorial:
Springer
Referencias:
Año: 2007 vol. 27 p. 717 - 729
ISSN:
0272-4340
Resumen:
(1) We evaluated the involvement of brain mitochondrial and microsomal
cytochrome P-450 in the metabolization of known porphyrinogenic agents, with the aim
of improving the knowledge on the mechanism leading to porphyric neuropathy. We
also compared the response in brain, liver and kidney. To this end, we determined
mitochondrial and microsomal cytochrome P-450 levels and the activity of NADPH
cytochrome P-450 reductase. (2) Animals were treated with known porphyrinogenic
drugs such as volatile anaesthetics, allylisopropylacetamide, veronal, griseofulvin and
ethanol or were starved during 24 h. Cytochrome P-450 levels and NADPH cytochrome
P-450 reductase activity were measured in mitochondrial and microsomal fractions
from the different tissues. (3) Some of the porphyrinogenic agents studied altered
mitochondrial cytochrome P-450 brain but not microsomal cytochrome P-450. Oral
griseofulvin induced an increase in mitochondrial cytochrome P-450 levels, while
chronic Isoflurane produced a reduction on its levels, without alterations on microsomal
cytochrome P-450. Allylisopropylacetamide diminished both mitochondrial and microsomal
cytochrome P-450 brain levels; a similar pattern was detected in liver.
Mitochondria cytochorme P-450 liver levels were only diminished after chronic
Isoflurane administration. In kidney only mitochondrial cytochrome P-450 levels were
modified by veronal; while in microsomes, only acute anaesthesia with Enflurane
diminished cytochrome P-450 content. (4) Taking into account that d-aminolevulinic
acid would be responsible for porphyric neuropathy, we investigated the effect of
acute and chronic d-aminolevulinic acid administration. Acute 5-aminolevulinic acid
administration reduced brain and liver cytochrome P-450 levels in both fractions;
chronic 5-aminolevulinic acid administration diminished only liver mitochondrial
cytochrome P-450. (5) Brain NADPH cytochrome P-450 reductase activity in animals
receiving allylisopropylacetamide, dietary griseofulvin and d-aminolevulinic acid
showed a similar profile as that for total cytochrome P-450 levels. The same response
was observed for the hepatic enzyme. (6) Results here reported revealed differential
tissue responses against the xenobiotics assayed and give evidence on the participation
of extrahepatic tissues in porphyrinogenic drug metabolization. These studies have
demonstrated the presence of the integral Phase I drug metabolizing system in the brain,
thus, total cytochrome P-450 and associated monooxygenases in brain microsomes and
mitochondria would be taken into account when considering the xenobiotic metabolizing
capability of this organ.