Role of Human CYP4F2 in Hepatic Catabolism of the Proinflammatory Agent Leukotriene B4

Jin, Rongyu; Koop, Dennis R.; Raucy, Judy L.; Lasker, Jerome M.

doi:10.1006/abbi.1998.0880

Cited by 63 publications

(61 citation statements)

References 37 publications

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“…Microsomal Enzyme Purification-CYP4F2, CYP4A11, b 5 , and P450 reductase were purified to electrophoretic homogeneity from human liver microsomes as reported elsewhere (38,40,41). The specific contents of the hemoproteins were 7.2 (CYP4F2), 12.6 (CYP4A11), and 29.6 (b 5 ) nmol/mg of protein, whereas the specific activity of P450 reductase was 25,800 units/mg; 1 unit of P450 reductase activity was defined as that amount catalyzing reduction of 1 nmol of ferricytochrome c/min at 22°C in 300 mM KPO 4 buffer (pH 7.7).…”

Section: Methodsmentioning

confidence: 99%

“…Immunochemical Methods-Polyclonal antibodies to human liver CYP4F2 and CYP4A11 were raised in male New Zealand White rabbits as described previously (36,38). Preimmune (control) IgG was prepared from rabbit sera obtained prior to immunization.…”

Section: Methodsmentioning

confidence: 99%

“…All immunochemical staining was performed under conditions where the peroxidase reaction density was directly proportional to the amount of protein applied to the original polyacrylamide gels. The contents of CYP4F2 and CYP4A11 in human liver microsomes were determined as described elsewhere (36,38).…”

Section: Methodsmentioning

confidence: 99%

“…1. The results shown with liver microsomes were taken from Powell et al (36) and/or Jin et al (38). catalysis by a single enzyme (or by two or more enzymes with similar kinetic properties).…”

Section: Aa Metabolism By Human Kidneymentioning

confidence: 99%

“…Indeed, it is intriguing that the P450 enzymes expressed in human kidney metabolize only endogenous substrates (e.g. fatty acids and leukotriene B4) (37,38) and not xenobiotics, which could explain any observed differences between humans and experimental animals in the kidney's susceptibility to nephrotoxins requiring bioactivation to exert their deleterious effects.…”

Section: -Hete Formation By Human Renal P450 Enzymesmentioning

confidence: 99%

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Formation of 20-Hydroxyeicosatetraenoic Acid, a Vasoactive and Natriuretic Eicosanoid, in Human Kidney

Lasker¹,

Chen²,

Wolf³

et al. 2000

Journal of Biological Chemistry

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284

265

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20-Hydroxyeicosatetraenoic acid (20-HETE), an -hydroxylated arachidonic acid (AA) metabolite, elicits specific effects on kidney vascular and tubular function that, in turn, influence blood pressure control. The human kidney's capacity to convert AA to 20-HETE is unclear, however, as is the underlying P450 catalyst. Microsomes from human kidney cortex were found to convert AA to a single major product, namely 20-HETE, but failed to catalyze AA epoxygenation and midchain hydroxylation. Despite the monophasic nature of renal AA -hydroxylation kinetics, immunochemical studies revealed participation of two P450s, CYP4F2 and CYP4A11, since antibodies to these enzymes inhibited 20-HETE formation by 65.9 ؎ 17 and 32.5 ؎ 14%, respectively. Western blotting confirmed abundant expression of these CYP4 proteins in human kidney and revealed that other AA-oxidizing P450s, including CYP2C8, CYP2C9, and CYP2E1, were not expressed. Immunocytochemistry showed CYP4F2 and CYP4A11 expression in only the S2 and S3 segments of proximal tubules in cortex and outer medulla. Our results demonstrate that CYP4F2 and CYP4A11 underlie conversion of AA to 20-HETE, a natriuretic and vasoactive eicosanoid, in human kidney. Considering their proximal tubular localization, these P450 enzymes may partake in pivotal renal functions, including the regulation of salt and water balance, and arterial blood pressure itself.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Aa Metabolism By Human Kidneymentioning

confidence: 99%

Section: -Hete Formation By Human Renal P450 Enzymesmentioning

confidence: 99%

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Formation of 20-Hydroxyeicosatetraenoic Acid, a Vasoactive and Natriuretic Eicosanoid, in Human Kidney

Lasker¹,

Chen²,

Wolf³

et al. 2000

Journal of Biological Chemistry

Self Cite

284

265

View full text Add to dashboard Cite

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CytochromeP450 Enzymes

Hrycay

Bandiera

2010

Pharmaceutical Sciences Encyclopedia

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The cytochrome P450 (CYP) enzymes, also known as the microsomal mixed function oxidase system, are the predominant biotransformation pathway in the body for lipid‐soluble endogenous and xenobiotic compounds. CYP enzymes play a key role in the biotransformation of pharmaceutical agents and thus are major determinants of duration of action and clearance of drugs. This article focuses on the characterization, function, and regulation of CYP enzymes that are relevant to our understanding of how CYP enzymes can metabolize a large variety of drugs.

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Comparative Intra‐Subject Analysis of Gene Expression and Protein Abundance of Major and Minor Drug Metabolizing Enzymes in Healthy Human Jejunum and Liver

Wenzel,

Lapczuk‐Romanska,

Malinowski

et al. 2023

Clin Pharma and Therapeutics

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First pass metabolism by phase I and phase II‐enzymes in the intestine and liver is a major determinant of the oral bioavailability of many drugs. Several studies analyzed expressions of major drug‐metabolizing enzymes (DMEs) such as CYP3A4 and UGT1A1 in the human gut and liver. However, there is still a lack of knowledge regarding other DMEs, i.e. “minor” DMEs, although several clinically relevant drugs are affected by those enzymes. Moreover, there is very limited intra‐subject data on hepatic and intestinal expression levels of minor DMEs. To fill this gap of knowledge, we analyzed gene expression (qRT‐PCR) and protein abundance (targeted proteomics) of 24 clinically relevant DMEs, i.e. carboxylesterases (CES), UDP‐glucuronosyltransferases (UGT) and cytochrome P450 (CYP)‐enzymes. We performed our analysis using jejunum and liver tissue specimens from the same 11 healthy organ donors (8 males, 3 females, aged 19‐60 y). Protein amounts of all investigated DMEs, with the exception of CYP4A11, were detected in human liver samples. CES2, CYP2C18, CYP3A4 and UGT2B17 protein abundance was similar or even higher in the jejunum, and all other DMEs were found in higher amounts in the liver. Significant correlations between gene expression and protein levels were observed only for 2 of 15 jejunal, but 13 of 23 hepatic DMEs. Intestinal and hepatic protein amounts only significantly correlated for CYP3A4 and UGT1A3. Our results demonstrated a notable variability between the individuals, which was even higher in the intestine than in the liver. Our intra‐subject analysis of DMEs in the jejunum and liver from healthy donors may be useful for PBPK‐based modelling and prediction in order to improve efficacy and safety of oral drug therapy.

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Role of Human CYP4F2 in Hepatic Catabolism of the Proinflammatory Agent Leukotriene B4

Cited by 63 publications

References 37 publications

Formation of 20-Hydroxyeicosatetraenoic Acid, a Vasoactive and Natriuretic Eicosanoid, in Human Kidney

Formation of 20-Hydroxyeicosatetraenoic Acid, a Vasoactive and Natriuretic Eicosanoid, in Human Kidney

CytochromeP450 Enzymes

Comparative Intra‐Subject Analysis of Gene Expression and Protein Abundance of Major and Minor Drug Metabolizing Enzymes in Healthy Human Jejunum and Liver

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