Brain Mitochondrial Cytochromes P450: Xenobiotic Metabolism, Presence of Multiple Forms and Their Selective Inducibility

Bhagwat, Shripad V.; Boyd, Michael R.; Ravindranath, Vijayalakshmi

doi:10.1006/abbi.1995.1344

Cited by 56 publications

(35 citation statements)

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“…Membrane preparations containing both mitochondria and microsomes were prepared from Neuro2a cells transfected with the cDNA of brain variant CYP2D7 because P450-mediated xenobiotic metabolism takes place in both microsomes and mitochondria in rat and human brain (13,21). The expressed brain variant CYP2D7 metabo- lized 10 M codeine to morphine alone, and norcodeine could not be detected (Fig.…”

Section: Rt-pcr and Immunoblotting Show The Presence Of Brainmentioning

confidence: 99%

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A Frameshift Mutation and Alternate Splicing in Human Brain Generate a Functional Form of the Pseudogene Cytochrome P4502D7 That Demethylates Codeine to Morphine

Pai

Kommaddi

Chinta

et al. 2004

Journal of Biological Chemistry

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A frameshift mutation 138delT generates an open reading frame in the pseudogene, cytochrome P4502D7 (CYP2D7), and an alternate spliced functional transcript of CYP2D7 containing partial inclusion of intron 6 was identified in human brain but not in liver or kidney from the same individual. mRNA and protein of the brain variant CYP2D7 were detected in 6 of 12 human autopsy brains. Genotyping revealed the presence of the frameshift mutation 138delT only in those human subjects who expressed the brain variant CYP2D7. Genomic DNA analysis in normal volunteers revealed the presence of functional CYP2D7 in 4 of 8 individuals. In liver, the major organ involved in drug metabolism, a minor metabolic pathway mediated by CYP2D6 metabolizes codeine (pro-drug) to morphine (active drug), whereas norcodeine is the major metabolite. In contrast, when expressed in Neuro2a cells, brain variant CYP2D7 metabolized codeine to morphine with greater efficiency compared with the corresponding activity in cells expressing CYP2D6. Morphine binds to -opioid receptors in certain regions of the central nervous system, such as periaqueductal gray, and produces pain relief. The brain variant CYP2D7 and -opioid receptor colocalize in neurons of the periaqueductal gray area in human brain, indicating that metabolism of codeine to morphine could occur at the site of opioid action. Histiospecific isoforms of P450 generated by alternate splicing, which mediate selective metabolism of pro-drugs within tissues, particularly the brain, to generate active drugs may play an important role in drug action and provide newer insights into the genetics of metabolism.Cytochrome P450 (EC 1.14.14.1; P450) 1 and associated monooxygenases, a family of heme proteins, are the principal class of drug-metabolizing enzymes. A supergene family encodes them, and the member proteins exist as multiple forms having distinct yet overlapping substrate specificities. Multiple forms of P450, which are selectively induced or inhibited by a variety of drugs, are known to exist in liver, the major organ involved in P450-mediated metabolism (1). However, the potential to generate active metabolite(s) at the site of action has generated interest in extrahepatic P450. This has prompted extensive investigations into the xenobiotic metabolizing capability of extrahepatic organs, such as lung, kidney, skin, and nasal epithelium, and the far reaching consequences of such metabolism, in situ, within specific cells in target organs have been recognized in laboratory animals (2) and humans (3). The preferential localization of drug-metabolizing enzymes within specific cell types in these organs renders such cells significantly capable of metabolizing drugs (4). Thus, even minor metabolic pathways of xenobiotic metabolism can produce major effects if they take place at the site of action. These observations have prompted investigation into P450-associated monooxygenases in brain with an effort to determine the capability of the brain to metabolize psychoactive drugs (5, 6). P450-mediated ...

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Section: Rt-pcr and Immunoblotting Show The Presence Of Brainmentioning

confidence: 99%

“…The appearance of multiple forms of P450 in brain and their selective inducibility by a variety of drugs and xenobiotics have also been identified (9,(12)(13)(14). CYP2D is one of the major forms of P450 present in both rat (15) and human brain (16).…”

mentioning

confidence: 99%

A Frameshift Mutation and Alternate Splicing in Human Brain Generate a Functional Form of the Pseudogene Cytochrome P4502D7 That Demethylates Codeine to Morphine

Pai

Kommaddi

Chinta

et al. 2004

Journal of Biological Chemistry

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“…Our studies showed the presence of five different xenobiotic-inducible P450 1 monooxygenases in rat liver mitochondria, which cross-react with antibodies to similarly induced microsomal P450 isoforms (9 -14). Enzyme reconstitution and immunochemical studies also showed the presence of several P450 isoforms, resembling the liver mitochondrial forms, in induced rat brain and human brain mitochondria (15)(16)(17). Additionally, reports from various groups have shown the occurrence of different isoforms of glutathione S-transferases in the mitochondrial membrane compartment of rat liver, brain, and lung (18 -21), suggesting the existence of both class I and class II enzymes in mitochondria.…”

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confidence: 99%

Physiological Role of the N-terminal Processed P4501A1 Targeted to Mitochondria in Erythromycin Metabolism and Reversal of Erythromycin-mediated Inhibition of Mitochondrial Protein Synthesis

Anandatheerthavarada

Vijayasarathy

Bhagwat

et al. 1999

Journal of Biological Chemistry

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Recently, we showed that the major species of ␤-naphthoflavone-inducible rat liver mitochondrial P450MT2 consists of N-terminal truncated microsomal P4501A1 (؉33/1A1) and that the truncated enzyme exhibits different substrate specificity as compared with intact P4501A1. The results of the present study show that P450MT2 targeted to COS cell mitochondria by transient transfection of P4501A1 cDNA is localized inside the mitochondrial inner membrane in a membrane-extrinsic orientation. Co-expression with wild type P4501A1 and adrenodoxin (Adx) cDNAs resulted in 5-7-fold higher erythromycin N-demethylation (ERND) in the mitochondrial fraction but minimal changes in the microsomal fraction of transfected cells. Erythromycin, a potent inhibitor of bacterial and mitochondrial protein synthesis, caused 8 -12-fold higher accumulation of CYP1A1 mRNA, preferential accumulation of P450MT2, and 5-6-fold higher ERND activity in the mitochondrial compartment of rat C6 glioma cells. Consistent with the increased mitochondrial ERND activity, co-expression with P4501A1 and Adx in COS cells rendered complete protection against erythromycin-mediated mitochondrial translation inhibition. Mutations that specifically affect the mitochondrial targeting of P4501A1 also abolished protection against mitochondrial translation inhibition. These results for the first time suggest a physiological function for the xenobiotic inducible cytochrome P4501A1 against drug-mediated mitochondrial toxicity.Mitochondria in mammalian organisms are important subcellular targets for a variety of xenobiotics including drugs, carcinogens, and environmental contaminants (1-6). Structurally diverse chemicals and pharmacologically important drugs, which alter mitochondrial membrane properties and affect mitochondrial enzyme complexes or gene expression, are thought to be contributing factors in a variety of human disorders (3,(5)(6)(7)(8). Efforts in our laboratory have been focused on the characterization of mitochondrial class I and class II drug metabolizing enzymes to determine their roles in modulating the toxic effects of various xenobiotic chemicals on the mitochondrial genetic system. Our studies showed the presence of five different xenobiotic-inducible P450 1 monooxygenases in rat liver mitochondria, which cross-react with antibodies to similarly induced microsomal P450 isoforms (9 -14). Enzyme reconstitution and immunochemical studies also showed the presence of several P450 isoforms, resembling the liver mitochondrial forms, in induced rat brain and human brain mitochondria (15-17). Additionally, reports from various groups have shown the occurrence of different isoforms of glutathione S-transferases in the mitochondrial membrane compartment of rat liver, brain, and lung (18 -21), suggesting the existence of both class I and class II enzymes in mitochondria.Recent studies in our laboratory showed that the two BNFinducible hepatic mitochondrial P450s, designated as P450MT2A and MT2B, are derived by differential proteolytic processing of the similarly...

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“…Further, chronic alcohol consumption induces liver injury in Cu, Zn-superoxide dismutase-de fi cient mice (Sod1−/−), with extensive centrilobular necrosis, in fl ammation and mitochondrial dysfunction (Kessova and Cederbaum 2007 ) . Garro et al ( 1981 ) , Arinç et al ( 2007 ) , Ma et al ( 1991 ) , Dey et al ( 2002Dey et al ( , 2005 , Kapoor et al ( 2006 ) , Khan et al ( 2011) , Anandatheerthavarada et al ( 1993 , Bhagwat et al ( 1995 ) , Huan and Koop ( 1999 ) , Roberts et al ( 1995 ) , and Zaluzny et al ( 1990 ) N-methyl formamide Lerche et al ( 1996) Diethylnitrosamine Lerche et al ( 1996) Nicotine Howard et al ( 2001 Regulation of Hepatic CYP2E1 Mediated by Pathophysiological Conditions Such as Obesity, Diabetes and Chemical Inducers Treatment of rats with the chemical inducer-4-methylpyrazole and streptozotocin which is commonly used to induce diabetes, increases CYP2E1 protein and catalytic activity and the values are additive for each inducer alone suggesting that diabetes may increase the susceptibility to toxins which are activated by CYP2E1, more so if pre-exposure to chemical inducers similar to 4-methylpyrazole, e.g., ethanol, isoniazid occurs (Wu and Cederbaum 1993a ) . Pyrazole and 4-methylpyrazole, inducers for hepatic CYP2E1 induce renal CYP2E1, through a post-transcriptional mechanism-possibly involving increased protein stabilization .…”

Section: Antioxidant Depletion Promotes Cyp2e1 Mediated Liver Injury:mentioning

confidence: 97%

Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario

Dey

2013

Subcellular Biochemistry

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Research on Cytochrome P450 2E1 (CYP2E1), a key enzyme in alcohol metabolism has been very well documented in literature. Besides the involvement of CYP2E1 in alcohol metabolism as illustrated through the studies discussed in the chapter, recent studies have thrown light on several other aspects of CYP2E1 i.e. its extrahepatic expression, its involvement in several diseases and pathophysiological conditions; and CYP2E1 mediated carcinogenesis and modulation of drug efficacy. Studies involving these interesting facets of CYP2E1 have been discussed in the chapter focusing on the recent observations or ongoing studies illustrating the crucial role of CYP2E1 in disease development and drug metabolism.

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Brain Mitochondrial Cytochromes P450: Xenobiotic Metabolism, Presence of Multiple Forms and Their Selective Inducibility

Cited by 56 publications

References 0 publications

A Frameshift Mutation and Alternate Splicing in Human Brain Generate a Functional Form of the Pseudogene Cytochrome P4502D7 That Demethylates Codeine to Morphine

A Frameshift Mutation and Alternate Splicing in Human Brain Generate a Functional Form of the Pseudogene Cytochrome P4502D7 That Demethylates Codeine to Morphine

Physiological Role of the N-terminal Processed P4501A1 Targeted to Mitochondria in Erythromycin Metabolism and Reversal of Erythromycin-mediated Inhibition of Mitochondrial Protein Synthesis

Cytochrome P450 2E1: Its Clinical Aspects and a Brief Perspective on the Current Research Scenario

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