Targeting of Splice Variants of Human Cytochrome P450 2C8 (CYP2C8) to Mitochondria and Their Role in Arachidonic Acid Metabolism and Respiratory Dysfunction

Bajpai, Prachi; Srinivasan, Satish; Ghosh, Jyotirmoy; Nagy, Leslie D.; Wei, Shouzou; Guengerich, F. Peter; Avadhani, Narayan G.

doi:10.1074/jbc.m114.583062

Cited by 12 publications

(10 citation statements)

References 56 publications

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“…However, it did metabolize smaller substrates such as arachidonic acid and dibenzylfluorescein. Furthermore, the variant generated higher levels of reactive oxygen species and showed a higher level of mitochondrial respiratory dysfunction than wild type CYP2C8, suggesting that the mitochondrially targeted variant 3 may contribute to oxidative stress in tissues (Bajpai et al, 2014).…”

Section: Expressionmentioning

confidence: 99%

“…Analysis of liver samples has recently shown that a nearly full-length form of CYP2C8 (wild type) and an N-terminal truncated splice variant 3 are expressed in mitochondria (Bajpai et al, 2014). Although the wildtype protein was detected only at low levels in mitochondria (,25%), variant 3 was primarily targeted to mitochondria and minimally to the endoplasmic reticulum.…”

Section: Expressionmentioning

confidence: 99%

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Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

et al. 2015

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Section: Expressionmentioning

confidence: 99%

Section: Expressionmentioning

confidence: 99%

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

et al. 2015

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“…partial localization in mitochondria and catalytic activity there [55, 71]. Studies from several groups showed that mitochondrial Adx (plus ADR) and bacterial ferredoxin (plus NADPH-ferredoxin reductase) could efficiently donate electrons to mitochondria-localized P450 1A1, 2E1, 2C8, 2B1, 2D6, 3A4, and 17A1 [5, 6, 9, 19, 59, 70], demonstrating that mitochondria-localized P450s are catalytically active. It was also shown that the N-terminal acidic domain of Adx interacted with mitochondria-localized P450 1A1 through charge-charge interaction [1].…”

Section: Roles Of Mitochondrial P450smentioning

confidence: 99%

“…It was also shown that the N-terminal acidic domain of Adx interacted with mitochondria-localized P450 1A1 through charge-charge interaction [1]. These Adx-interacting domains are conserved in other P450 Family 1 members and also in P450s 2B1, 2B4, 2D6, 2E1, 3A4, 17A1, and 21A2 [5, 6, 9, 46, 59, 70]. …”

Section: Roles Of Mitochondrial P450smentioning

confidence: 99%

Roles of Cytochrome P450 in Metabolism of Ethanol and Carcinogens

Guengerich

Avadhani

2018

Advances in Experimental Medicine and Biology

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Cytochrome P450 (P450) enzymes are involved in the metabolism of carcinogens, as well as drugs, steroids, vitamins, and other classes of chemicals. P450s also oxidize ethanol, in particular P450 2E1. P450 2E1 oxidizes ethanol to acetaldehyde and then to acetic acid, roles also played by alcohol and aldehyde dehydrogenases. The role of P450 2E1 in cancer is complex in that P450 2E1 is also induced by ethanol, P450 2E1 is involved in the bioactivation and detoxication of a number of chemical carcinogens, and ethanol is an inhibitor of P450 2E1. Contrary to some literature, P450 2E1 expression and induction itself does not cause global oxidative stress in vivo, as demonstrated in studies using isoniazid treatment and gene deletion studies with rats and mice. However, a major fraction of P450 2E1 is localized in liver mitochondria instead of the endoplasmic reticulum, and studies with site-directed rat P450 2E1 mutants and natural human P450 2E1 N-terminal variants have shown that P450 2E1 localized in mitochondria is catalytically active and more proficient in producing reactive oxygen species and damage. The role of the mitochondrial oxidative stress in ethanol toxicity is still under investigation, as is the mechanism of altered electron transport to P450s that localize inside mitochondria instead of their typical endoplasmic reticulum environment.

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“…Bimodal targeting to both mitochondria and ER have been reported for CYP2C8 and several other P450s, including CYP1A1, 1B1, 2B1, 2E1, and 2D6. Although it is clear that alternative splicing directs this process in some tissues, proteolytic cleavage of N-terminal targeting sequences can also produce this effect (Bajpai et al, 2014). One 2C8 variant (variant 3; ;44 kDa) with an alternative N-terminus is targeted to the mitochondria, where it may contribute to oxidative stress (Bajpai et al, 2014).…”

Section: Meta-analysis Of Alternative Gene Splicing In the Cytochromementioning

confidence: 99%

Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism

2017

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The human genome encodes 57 cytochrome P450 genes, whose enzyme products metabolize hundreds of drugs, thousands of xenobiotics, and unknown numbers of endogenous compounds, including steroids, retinoids, and eicosanoids. Indeed, P450 genes are the first line of defense against daily environmental chemical challenges in a manner that parallels the immune system. Several National Institutes of Health databases, including PubMed, AceView, and Ensembl, were queried to establish a comprehensive analysis of the full human P450 transcriptome. This review describes a remarkable diversification of the 57 human P450 genes, which may be alternatively processed into nearly 1000 distinct mRNA transcripts to shape an individual's P450 proteome. Important P450 splice variants from families 1A, 1B, 2C, 2D, 3A, 4F, 19A, and 24A have now been documented, with some displaying alternative subcellular distribution or catalytic function directly linked to a disease pathology. The expansion of P450 transcript diversity involves tissue-specific splicing factors, transformation-sensitive alternate splicing, -splicing between gene transcripts, single-nucleotide polymorphisms, and epigenetic regulation of alternate splicing. Homeostatic regulation of variant P450 expression is influenced also by nuclear receptor signaling, suppression of nonsense-mediated decay or premature termination codons, mitochondrial dysfunction, or host infection. This review focuses on emergent aspects of the adaptive gene-splicing process, which when viewed through the lens of P450-nuclear receptor gene interactions, resembles a primitive immune-like system that can rapidly monitor, respond, and diversify to acclimate to fluctuations in endo-xenobiotic exposure. Insights gained from this review should aid future drug discovery and improve therapeutic management of personalized drug regimens.

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Targeting of Splice Variants of Human Cytochrome P450 2C8 (CYP2C8) to Mitochondria and Their Role in Arachidonic Acid Metabolism and Respiratory Dysfunction

Cited by 12 publications

References 56 publications

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

Roles of Cytochrome P450 in Metabolism of Ethanol and Carcinogens

Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism

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