Formation of 19(S)-, 19(R)-, and 18(R)-hydroxyeicosatetraenoic acids by alcohol-inducible cytochrome P450 2E1

Laethem, Ronald M.; Balazy, Michael; Falck, John R.; Laethem, Carmen; Koop, Dennis R.

doi:10.1016/s0021-9258(18)31472-8

Cited by 183 publications

(15 citation statements)

References 2 publications

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“…We observed a slight decrease in arachidonic acid epoxygenase activity in renal cortical microsomes from DHA-fed rats. Renal arachidonic acid epoxide formation is catalyzed by CYP2C23, CYP2E1, and CYP2J3 (33)(34)(35). The activity of one or more of these isoforms may be altered by DHA feeding and the reduction in arachidonic acid availability.…”

Section: Discussionmentioning

confidence: 99%

Docosahexaenoic Acid is an Antihypertensive Nutrient That Affects Aldosterone Production in SHR

Engler

Goodfriend

et al. 1999

Experimental Biology and Medicine

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The effects of dietary docosahexaenoic acid (DHA), an -3 polyunsaturated fatty acid, on blood pressure and some pressure-regulating systems were measured in young spontaneously hypertensive rats (SHR). Plasma aldosterone and corticosterone levels, adrenal aldosterone production in vitro, and characteristics of adrenal angiotensin receptors were measured after 6 weeks of diet. Renal cytochrome P450 (CYP) 4A gene expression and arachidonic acid metabolism by renal microsomes were also investigated. Plasma cholesterol, triglycerides, and high-density lipoprotein cholesterol were measured. Diets contained either corn/soybean oil alone (CSO), or oil enriched with DHA. After 6 weeks, rats fed DHA had systolic blood pressures averaging 34 mmHg less than controls (P < 0.001). Plasma aldosterone levels were 33% lower in the DHA-fed animals than in controls (22 ± 3 vs. 33 ± 3.7 ng/dl, P < 0.05). Plasma levels of corticosterone were 18% lower in animals fed DHA than in controls, but this difference was not statistically significant. Adrenal glomerulosa cells from DHA-fed rats produced less aldosterone in vitro in response to angiotensin II, ACTH, or potassium. The difference was less marked when aldosterone production was stimulated by supplying exogenous corticosterone, suggesting an effect of DHA on postreceptor steps in signal transduction or the early pathway of aldosteronogenesis. We found no significant differences in angiotensin receptor subtype, number, or affinity. Production of arachidonic epoxides by renal microsomes was 17% lower in DHA-fed animals than in controls (P < 0.05). Renal cortical mRNA levels of CYP4A genes and formation of 19-and 20-hydroxyeicosatetraenoic acid (HETE) did not differ between dietary groups. Plasma total cholesterol and high-density-lipoprotein (HDL) levels were significantly reduced in SHR fed the DHA supplement, but triglyceride levels were not significantly different. The effects of DHA on steroid and eicosanoid metabolism may be part of the mechanism by which this fatty acid prevents some of the hypertension in growing SHR.

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Section: Discussionmentioning

confidence: 99%

Docosahexaenoic Acid is an Antihypertensive Nutrient That Affects Aldosterone Production in SHR

Engler

Goodfriend

et al. 1999

Experimental Biology and Medicine

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“…Oleic acid is an unsaturated physiological fatty acid released from the sn-2 position of phospholipids, such as arachidonic acid. However, its metabolism, through the mammalian P450 pathway, has not been subjected to detailed study as has arachidonic acid (21,22,38). In order to investigate and identify the nature of the P450 enzyme involved in the hydroxylations of oleic acid by human and rat liver microsomes, five in vitro approaches were used, namely induction effect in rats, correlation studies between specific P450 activities in a panel of 25 human livers, chemical and immuno-inhibitions, and metabolism by cDNA-expressed human P450 enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…The turnover of the enzyme was lower than with lauric acid (7.8 min Ϫ1 ) (6), suggesting that, among the fatty acids examined, lauric acid was a most appropriate substrate for CYP2E1. Laethem et al (21) reported also that cytochrome P450 2E1, when reconstituted with cytochrome b5 and NADPH cytochrome P450 oxidoreductase, was able to metabolize lauric, stearic, oleic, linoleic, linolenic, and arachidonic acids to hydroxylated metabolites. A previous study (49) re- Results are expressed as turnover number (min Ϫ1 or pmol/min per mg of P450) and resulted from the mean Ϯ SD of two individual experiments.…”

Section: Discussionmentioning

confidence: 99%

“…Although oleic acid is released at a much lower level than arachidonic acid, it is proposed to be a more important messenger for sustained activation of PKC, as arachidonic acid is a polyunsaturated fatty acid and is therefore more quickly metabolized than oleic acid (17). In addition to the and ( -1)-hydroxylation products, unsaturated fatty acids are generally converted to epoxides by P450 monooxygenases (20)(21)(22). However, the epoxide pathway appears to be only a minor microsomal oxidation route for monounsaturated fatty acids such as oleic acid (22).…”

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confidence: 99%

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Involvement of cytochrome P450 2E1 in the (ω–1)-hydroxylation of oleic acid in human and rat liver microsomes

Adas

Berthou

Picart

et al. 1998

Journal of Lipid Research

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In vitro techniques have been used to investigate the nature of microsomal cytochrome P450 involved in the metabolism of oleic acid, a physiological monounsaturated fatty acid. Like lauric acid, which is cur rently used as a model substrate of fatty acid metabolism, the alkyl chain of oleic acid is hydroxylated on its and ( -1) carbons. The identity of these hydroxylated metabolites was ascertained by GC/MS and LC/MS. The / -1 ratio of oleic acid metabolites (1.22 ؎ 0.01) was found to be similar to that obtained with lauric acid in rat liver microsomes (1.10 ؎ 0.02), while in human liver microsomes this ratio was 0.75 ؎ 0.5 for lauric acid and 5.2 ؎ 2.6 for oleic acid. After treatment of rats with ethanol or clofibrate, inducers of CYP2E1 and CYP4A, respectively, the hydroxylations of oleic acid were shown to be less inducible than those of lauric acid. Five in vitro approaches were used to identify the P450 isoform(s) responsible for the microsomal ( -1)-hydroxylation of oleic acid: effect of various inducers in rats, correlation studies between specific P450 catalytic activities in a panel of 25 human liver microsomes, chemical inhibitions, immuno-inhibitions and metabolism by cDNA-expr essed human P450 enzymes. From the above results, it can be ascertained that P450 2E1 is the main enzyme involved in the ( -1)-hydroxylation of oleic acid. Furthermore, the -hydroxylation of oleic acid was shown to be mainly catalyzed by P450 4A enzymes in human liver microsomes. The turnover number of ( -1)-hydroxylation of lauric and oleic acids decreased from 7.8 to 1.5 min Ϫ 1 , respectively, suggesting that the dodecane alkyl chain allows optimal binding to the active site of CYP2E1.-Adas, F., F. Berthou, D. Picart, P. Lozac'h, F. Beaugé, and Y. Amet. Involvement of cytochrome P450 2E1 in the ( -1)-hydroxylation of oleic acid in human and rat liver microsomes.

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“…The metabolism of AA to 18(R)-OH-AA by microsomal fractions isolated from monkey seminal vesicles has been shown (19). Finally, purified P450 2E1, an isoform induced in rat liver by diabetes, fasting and alcohol, converted AA to 19(S)-and 18(R)-OH-AA (with 72 and nearly 100% optical purity, respectively) as its major reaction products (78).…”

Section: B Hydroxylations At C 16-c 20 ( / -1 Hydroxylase Reaction) the Aa / -1 Hydroxylasementioning

confidence: 98%

Cytochrome P450 and arachidonic acid bioactivation: molecular and functional properties of the arachidonate monooxygenase

Capdevila

Falck

Harris

2000

Journal of Lipid Research

479

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The demonstration of in vivo arachidonic acid epoxidation and -hydroxylation established the cytochrome P450 epoxygenase and / -1 hydroxylase as formal metabolic pathways and as members of the arachidonate metabolic cascade. The characterization of the potent biological activities associated with several of the cytochrome P450-derived eicosanoids suggested new and important functional roles for these enzymes in cellular, organ, and body physiology, including the control of vascular reactivity and systemic blood pressures. Past and current advances in cytochrome P450 biochemistry and molecular biology facilitate the characterization of cytochrome P450 isoforms responsible for tissue/organ specific arachidonic acid epoxidation and / -1 hydroxylation, and thus, the analysis of cDNA and/or gene specific functional phenotypes. The combined application of physiological, biochemical, molecular, and genetic approaches is beginning to provide new insights into the physiological and/or pathophysiological significance of these enzymes, their endogenous substrates, and products. -Capdevila,

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Formation of 19(S)-, 19(R)-, and 18(R)-hydroxyeicosatetraenoic acids by alcohol-inducible cytochrome P450 2E1

Cited by 183 publications

References 2 publications

Docosahexaenoic Acid is an Antihypertensive Nutrient That Affects Aldosterone Production in SHR

Docosahexaenoic Acid is an Antihypertensive Nutrient That Affects Aldosterone Production in SHR

Involvement of cytochrome P450 2E1 in the (ω–1)-hydroxylation of oleic acid in human and rat liver microsomes

Cytochrome P450 and arachidonic acid bioactivation: molecular and functional properties of the arachidonate monooxygenase

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