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

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 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.

Xenobiotic-Metabolizing Enzymes and Transporters in the Normal Human Brain: Regional and Cellular Mapping as a Basis for Putative Roles in Cerebral Function

“…This level of detail was not available for the majority of P450s. Finally, we assessed the presence of cytochrome P450 reductase (CRP) and ferredoxin reductase (FDXR) enzymes, which is a prerequisite for a functional enzymatic system (Bhagwat et al, 2000;Lavandera et al, 2007). Our results support the existence of active enzymes, as previously documented in human and rodent brain by measurement of microsomal monooxygenase activities and enzyme inhibition method (Miksys and Tyndale, 2009).…”

Exposure to benzidine caused apoptosis and malformation of telencephalon region in zebrafish

“…The latter is considered a detoxification product, while N‐acetylbenzidine is oxidized to reactive intermediates that form DNA adducts (Choudhary, ), it will cause the organism to DNA damage, cell abnormal proliferation, tissue pathological change, even more to cancer. Both brain tissue impairment and neuron degeneration are some pathological lesions and may be due to an unexplored detoxification mechanism or to phagocytosis of cellular debris resulting from apoptosis when animal take some xenobiotic chemical such as synthetic azo dye (Ravindranath et al, ; Lavandera et al, ; Milbury and Kalt, ).…”

“…In developing countries, there has been an increasing concern as to the potential health effects of xenobiotics, including polycyclic aromatic hydrocarbons (PAHs), dioxin, pesticides, arylamine, and synthetic drugs, because these compounds have been associated with tissue dysfunction in a variety of species (Hill et al, ; Janosek et al, ; Scott et al, ). Although many valuable instruments can detect these xenobiotics in the environment, a traditional LC 50 offers scarce information regarding the actual impact on an organism at sublethal doses, such as cancer from benzidine exposure, infertility from 17α‐ethynylestradiol exposure, and brain neuropathy (Lotti, ; Lavandera et al, ; Vosges et al, ; Wang et al, ). The zebrafish is a popular animal model for the study of developmental toxicity because of its wide availability, transparent embryos, and well‐known genetic background (Hill et al, ).…”

Expressions of genes encoding drug-metabolizing enzymes are altered after sevoflurane, isoflurane, propofol or dexmedetomidine anesthesia

“…General anesthesia has been routinely used for surgical operations, and its safety has been assessed and established by clinical outcomes for sevoflurane (18), isoflurane (16), propofol (17) and dexmedetomidine (7). However, only a few studies have reported on the effects of anesthesia at the molecular level (2,15,19,25). Halothane (CF 3 CHBrCl), sevoflurane (CHF 2 -O-CHF-CF 3 ) and isoflurane (CHF 2 -O-CHCl-CF 3 ) are halogenated inhalation anesthetics that are metabolized by hepatic cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1) (13,14).…”