Metabolization of porphyrinogenic agents in brain: involvement of the phase I drug metabolizing system. A comparative study in liver and kidney.
(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 cytochrome 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 delta-aminolevulinic acid would be responsible for porphyric neuropathy, we investigated the effect of acute and chronic delta-aminolevulinic acid administration. Acute delta-aminolevulinic acid administration reduced brain and liver cytochrome P-450 levels in both fractions; chronic delta-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 delta-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.
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), CONICET, Hospital de Clínicas José de San Martín, University of Buenos Aires, Buenos Aires, Argentina.
Jimena V
JV
Lavandera
Alcira Maria Del Carmen
AM
Batlle
Ana María
AM
Buzaleh
D000502:Allylisopropylacetamide / Q000493:pharmacokinetics; D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D001462:Barbital / Q000493:pharmacokinetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D000431:Ethanol / Q000493:pharmacokinetics; D006118:Griseofulvin / Q000493:pharmacokinetics; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D050216:Metabolic Detoxication, Phase I / Q000502:physiology; D051379:Mice; D008861:Microsomes / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D017319:Photosensitizing Agents / Q000493:pharmacokinetics; D017118:Porphyria, Acute Intermittent / Q000139:chemically induced* / Q000378:metabolism
D006993:Hypnotics and Sedatives; D017319:Photosensitizing Agents; D000502:Allylisopropylacetamide; D006118:Griseofulvin; D000431:Ethanol; D001462:Barbital; D000622:Aminolevulinic Acid; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase