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Metabolization of Porphyrinogenic Agents in Brain: Involvement of the Phase I Drug Metabolizing System. A Comparative Study in Liver and Kidney

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Abstract

(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 δ-aminolevulinic acid would be responsible for porphyric neuropathy, we investigated the effect of acute and chronic δ-aminolevulinic acid administration. Acute δ-aminolevulinic acid administration reduced brain and liver cytochrome P-450 levels in both fractions; chronic δ-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 δ-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.

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Acknowledgements

A. M. Buzaleh and A. Batlle hold the post of Associated and Superior Scientific Researchers at the Argentine National Research Council (CONICET). J. Lavandera was a Fellow from the Argentine Scientific and Technologic Agency (ASTA). This work has been supported by grants from the CONICET, the ASTA and the University of Buenos Aires, Argentina.

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Authors and Affiliations

  1. Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET, Hospital de Clínicas José de San Martín, University of Buenos Aires, Viamonte 188l 10°, “A”, C1056ABA, Buenos Aires, Argentina

    Jimena V. Lavandera, Alcira Maria Del Carmen Batlle & Ana María Buzaleh

  2. Department of Biological Chemistry, Facultad de Ciencias Exactas y Naturales, University of Buenos Aires, Buenos Aires, Argentina

    Ana María Buzaleh

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  1. Jimena V. Lavandera
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  2. Alcira Maria Del Carmen Batlle
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  3. Ana María Buzaleh
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Correspondence to Alcira Maria Del Carmen Batlle.

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Dedicated to the memory of Dr. Susana Afonso

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Lavandera, J.V., Batlle, A.M.D.C. & Buzaleh, A.M. Metabolization of Porphyrinogenic Agents in Brain: Involvement of the Phase I Drug Metabolizing System. A Comparative Study in Liver and Kidney. Cell Mol Neurobiol 27, 717–729 (2007). https://doi.org/10.1007/s10571-007-9154-0

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  • DOI: https://doi.org/10.1007/s10571-007-9154-0

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