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PubMed1984

Autocatalytic inactivation of plant cytochrome P-450 enzymes: selective inactivation of the lauric acid in-chain hydroxylase from Helianthus tuberosus L. by unsaturated substrate analogs.

Lauric acid in-chain hydroxylation is inhibited in microsomes from Jerusalem artichoke tubers (Helianthus tuberosus L.) incubated with 9-decenoic, 11-dodecenoic, or 11-dodecynoic acids. 9-Decenoic acid is at best a weak competitive inhibitor of the in-chain hydroxylase, but inactivates the enzyme in a time-dependent, pseudo-first-order process with a rate constant of approximately 1.1 X 10(-3) s-1. In contrast, 11-dodecenoic acid causes a slower, time-dependent loss of the hydroxylase activity, but is a potent competitive inhibitor of the enzyme (Ki = 2 microM). Neither agent decreases the microsomal concentration of cytochrome b5, NADH-cytochrome b5 reductase, or NADPH cytochrome P-450 reductase. Cinnamic acid 4-hydroxylation, catalyzed by a cytochrome P-450 enzyme, is not affected by concentrations of 9-decenoic acid that suppress lauric acid hydroxylation. 11-Dodecenoic acid is much less specific and, at higher concentrations, markedly reduces the microsomal cytochrome P-450 content, and the hydroxylation of both lauric and cinnamic acids.

Binding, Competitive↗
PubMed1977

Effects of maternal dodecanoic or lauric acid (C12:0) feeding on milk fatty acid secretion and lipogenesis in the suckling rat.

Lauric acid feeding induced large alterations in mammary gland fatty acid secretion. It was highly incorported in milk triglycerides, suggesting that mammary gland was not able to efficiently regulate the qualitative aspects of medium-chain fatty acid secretion. These modifications in milk fatty acid secretion did not alter pup growth, lipogenesis balance or the classic parameters of the pup liver during the suckling period. Nevertheless, maternal lauric acid feeding induced important alterations in the qualitative aspects of pup lipogenesis before weaning.

Animal Feed↗
PubMed1995

Biochemical characterization of lauric acid omega-hydroxylation by a CYP4A1/NADPH-cytochrome P450 reductase fusion protein.

The binding and hydroxylation of lauric acid by a genetically engineered and expressed fusion protein comprised of an N-truncated form of rat CYP4A1 linked to an N-truncated form of rat NADPH cytochrome P450 oxidoreductase (OR) (constructed by Fisher et al., (1992) Proc. Natl. Acad. Sci. USA 89, 10817-10822) has been characterized biochemically and compared to that shown by purified reconstituted rat CYP4A1 and liver microsomes from clofibrate-induced rats. In all systems lauric acid induced a Type I cytochrome P450 difference spectrum with Ks values in agreement with prior literature (range 10-18 microM). When provided with NADPH and oxygen but no other proteins or lipid, the fusion protein (called f4A1) catalyzed omega-hydroxylation of lauric acid with apparent Km and Vm of 3-4 microM and 4-5 nmol product/min/nmol P450 irrespective of buffer concentration or cation (NaPi or KPi, 25-200 mM); comparable values for reconstituted CYP4A1 and microsomes from clofibrate-induced rats are 9 microM and 34 min-1 and 5 microM and 10 min-1, respectively. (omega-1)-Hydroxylation of lauric acid was barely detectable (omega/(omega-1) = 135) with f4A1 or with reconstituted CYP4A1, but it accounted for up to 50% of total products formed by microsomes from clofibrate-induced rats. When added to the f4A1 system, OR stimulated hydroxylation up to fivefold at a OR:f4A1 ratio of 5:1; additionally, (omega-1)-hydroxylation was routinely observed as a minor process (< 4% of total product) in this system. These effects were also independent of buffer concentration. In contrast addition of cytochrome b5 (b5) caused a small (25%) decrease in omega-hydroxylation, while added phospholipid had no effect. However, the combination of OR, b5, and lipid stimulated turnover approximately 10-fold compared to f4A1 alone, and 11-hydroxylauric acid was regularly formed as a minor (3-4% of total) product. These observations indicate that the fusion protein f4A1 is functionally equivalent to reconstituted CYP4A1 with respect to binding and hydroxylation of lauric acid and suggest that it can be used as an alternative to reconstituted systems for structure-function and mechanistic studies of fatty acid omega-hydroxylation.

Animals↗
PubMed2006

Determination of CYP4A11-catalyzed lauric acid 12-hydroxylation by high-performance liquid chromatography with radiometric detection.

Lauric acid serves as an endogenous substrate for the cytochrome P450 enzyme CYP4A11. A reverse-phase, high-performance liquid chromatography method is described for the quantification of 12-hydroxylauric acid formed enzymatically by incubation of 14C-labeled lauric acid with cDNA-expressed CYP4A11 or human liver microsomes. Analytical separation is achieved using a C18 column and a gradient of 30% acetonitrile and 2 mM perchloric acid to 100% methanol, using a detection scintillation counter. This method is applicable to enzymatic studies for determination of lauric acid 12-hydroxylation activity.

Catalysis↗
PubMed1998

Induction of lauric acid hydroxylase activity in catfish and bluegill by peroxisome proliferating agents.

In mammals, sensitivity to peroxisome proliferation by peroxisome proliferating agents (PPAs) appears to be correlated with inducibility of lauric acid hydroxylase activity. Bluegill and catfish have been shown to respond to PPAs by induction of lauric acid hydroxylase immunoreactive proteins (Haasch, 1996). In this investigation, induction of lauric acid hydroxylase activity was confirmed by HPLC and mass spectral analysis of specific hydroxylation products and possible species-specific differences in metabolism were investigated. Male bluegill, channel catfish and rat, were administered the model PPAs, clofibrate (200 mg kg-1, i.p.), ciprofibrate (100 mg kg-1, i.p.), or olive oil as vehicle control (both sexes of catfish), 48 h prior to hepatic, trunk kidney (catfish only) or kidney (rat) microsome preparation. In general, total metabolism of lauric acid was similar in all species, but female catfish metabolize lauric acid to a greater extent than males. Ciprofibrate treatment produced significant induction of omega- and omega-6 hydroxylation in male catfish kidney. In male bluegill liver, omega-, omega-4 and omega-5 hydroxylations were significantly induced by clofibrate treatment. The data indicate that induction of lauric acid hydroxylase cytochrome(s) P450 occurs in PPA-exposed fish which may be a consideration for environmentally-exposed responsive species.

Animals↗
PubMed1993

Hydrophobic side chain requirements for lauric acid and progesterone hydroxylation at amino acid 113 in cytochrome P450 2C2, a potential determinant of substrate specificity.

To determine the requirements for hydrophobic amino acids at position 113 in cytochrome P450 2C2, a series of hydrophobic and uncharged polar amino acids was substituted for isoleucine in P450 2C2 and in C2MstC1, a chimera of P450 2C2 and P450 2C1. Lauric acid hydroxylase activity was determined in COS1 cells transfected with P450 2C2 mutants and both lauric acid and progesterone hydroxylase activities were determined for C2MstC1 variants. In P450 2C2, 40 to 120% of the wild type (omega-1) lauric acid hydroxylase activity was retained in all hydrophobic mutants, but activity was reduced to near background by substitutions of the polar amino acids, tyrosine and cysteine. Likewise, in C2MstC1 mutants, hydrophobic substitutions were 20 to 50% as active as wild type for lauric acid hydroxylation, and polar amino acids again resulted in strong reductions of activity. In contrast, a different pattern of activity for progesterone C21-hydroxylase was observed for C2MstC1 mutants. A valine substitution had a modest effect on activity but substitutions of leucine and alanine reduced progesterone C21-hydroxylase activity 5- to 7-fold, respectively, and the large hydrophobic amino acid, phenylalanine, reduced activity about 30-fold. No changes in the regiospecificity of progesterone hydroxylation were observed for any of the mutants. Similar steady-state levels of immunoprecipitated, radiolabeled protein were observed for each mutant except for the glycine substitution which resulted in degradation of the protein. The different patterns of the effects of the mutations on progesterone and lauric acid hydroxylase activity provide additional support for the critical role of residue 113 in substrate recognition. The low activities in mutant proteins with hydrophilic amino acid substitutions indicate that the hydrophobic nature of this residue is important. The hydrophobic requirements are more stringent for a larger, more rigid steroid substrate than for a saturated fatty acid with a flexible hydrocarbon tail.

Amino Acid Sequence↗
PubMed1992

Subterminal hydroxylation of lauric acid by microsomes from a marine fish.

Microsomes from the liver of sea bass (Dicentrarchus labrax) were shown to hydroxylate lauric acid at subterminal positions. The cytochrome P-450 system converted lauric acid to several mono-hydroxylated metabolites including omega-1 hydroxylaurate, which was the major metabolite (44% of total products). In addition, omega-2, omega-3, omega-4 and a small amount (2.3%) of omega hydroxylaurates were found. Reaction products were identified using thin-layer chromatography (TLC) and gas chromatography/mass spectrometry (GC/MS). Oxidation reactions were dependent upon O2 and NADPH, and did not occur with boiled microsomes or in the presence of a mixture of CO/O2. Hydroxylation proceeded linearly up to 20 min at 28 degrees C for protein concentrations below 380 micrograms. Treatment of fish with benzo(a)pyrene (BP) (20 mg/kg) drastically increased xenobiotic metabolism (ECOD, EROD and BPMO activities), but no difference in laurate hydroxylase activity was observed between untreated and treated fish. Starvation strongly enhanced laurate hydroxylase activity, and resumption of feeding reduced by half this increase of activity. In all of the experiments we did not observe any modification of the regioselectivity of lauric acid hydroxylation by this microsomal in-chain hydroxylating system. We suggest that cytochrome P-450 enzymes involved in lauric acid and xenobiotics metabolism are regulated independently.

Animals↗
PubMed2003

Effect of lauric acid on transdermal penetration of phenazepam in vivo.

We studied the effect of lauric acid on transdermal penetration of phenazepam in vivo. It was found that treatment with lauric acid 3-fold increased the maximum anticonvulsive effect of phenazepam applied in a transdermal therapeutic system in comparison with the control. Study of the pharmacokinetics of phenazepam transdermal therapeutic system showed its higher bioavailability in the presence of lauric acid (f=0.9).

Administration, Cutaneous↗
PubMed1997

Suicide inactivation of cytochrome P450 by midchain and terminal acetylenes. A mechanistic study of inactivation of a plant lauric acid omega-hydroxylase.

Incubation of Vicia sativa microsomes, containing cytochrome P450-dependent lauric acid omega-hydroxylase (omega-LAH), with [1-(14)C]11-dodecynoic acid (11-DDYA) generates a major metabolite characterized as 1,12-dodecandioic acid. In addition to time- and concentration-dependent inactivation of lauric acid and 11-DDYA oxidation, irreversible binding of 11-DDYA (200 pmol of 11-DDYA bound/mg of microsomal protein) at a saturating concentration of 11-DDYA was observed. SDS-polyacrylamide gel electrophoresis analysis showed that 30% of the label was associated with several protein bands of about 53 kDa. The presence of beta-mercaptoethanol in the incubate reduces 1,12-dodecandioic acid formation and leads to a polar metabolite resulting from the interaction of oxidized 11-DDYA with the nucleophile. Although the alkylation of proteins was reduced, the lauric acid omega-hydroxylase activity was not restored, suggesting an active site-directed inactivation mechanism. Similar results were obtained when reconstituted mixtures of cytochrome P450 from family CYP4A from rabbit liver were incubated with 11-DDYA. In contrast, both 11- and 10-DDYA resulted in covalent labeling of the cytochrome P450 2B4 protein and irreversible inhibition of activity. These results demonstrate that acetylenic analogues of substrate are efficient mechanism-based inhibitors and that a correlation between the position of the acetylenic bond in the inhibitor and the regiochemistry of cytochromes P450 oxygenation is essential for enzyme inactivation.

Acetylene↗
PubMed2002

Lauric acid is desaturated to 12:1n-3 by hepatocytes and rat liver homogenates.

Lauric acid desaturation was investigated and described in liver homogenates and in cultured rat hepatocytes. The identification of the desaturated product of lauric acid has been performed using the oxidative cleavage method, and we showed that the obtained monoene was mainly 12:1n-3. This result suggests that lauric acid desaturation could be the first step in the biosynthesis of alpha-linolenic acid in animal cells.

Animals↗
PubMed2004

Drosophila melanogaster CYP6A8, an insect P450 that catalyzes lauric acid (omega-1)-hydroxylation.

Only a handful of P450 genes have been functionally characterized from the approximately 90 recently identified in the genome of Drosophila melanogaster. Cyp6a8 encodes a 506-amino acid protein with 53.6% amino acid identity with CYP6A2. CYP6A2 has been shown to catalyze the metabolism of several insecticides including aldrin and heptachlor. CYP6A8 is expressed at many developmental stages as well as in adult life. CYP6A8 was produced in Saccharomyces cerevisiae and enzymatically characterized after catalytic activity was reconstituted with D. melanogaster P450 reductase and NADPH. Although several saturated or non-saturated fatty acids were not metabolized by CYP6A8, lauric acid (C12:0), a short-chain unsaturated fatty acid, was oxidized by CYP6A8 to produce 11-hydroxylauric acid with an apparent V(max) of 25 nmol/min/nmol P450. This is the first report showing that a member of the CYP6 family catalyzes the hydroxylation of lauric acid. Our data open new prospects for the CYP6 P450 enzymes, which could be involved in important physiological functions through fatty acid metabolism.

Aldrin↗
PubMed1998

P-450-dependent metabolism of lauric acid in alcoholic liver disease: comparison between rat liver and kidney microsomes.

Monooxygenase enzymatic activities were measured in liver and kidney microsomes of control and ethanol-treated rats. Animals were administered alcohol by using a model for alcoholic liver injury. Several in vitro approaches were used to compare the laurate metabolism in liver and kidney microsomes: correlation studies between specific P-450 catalytic activities, immunoblot analysis, and chemical and immunoinhibitions. Ethanol treatment increased the liver and renal hydroxylations of chlorzoxazone and 4-nitrophenol. Moreover, lauric acid (omega-1)-hydroxylation was found to be significantly increased (-6-fold) after ethanol treatment in liver, but not in kidney microsomes. The laurate omega-1/omega ratio increased from 1.52 +/- 0.49 to 4.11 +/- 1.01 in liver microsomes of control and ethanol-treated rats, and from 0.29 +/- 0.06 to 0.44 +/- 0.07 in kidney microsomes. Immunoblot analysis using polyclonal anti-cytochrome P-450 (CYP) 2E1 or CYP4A antibodies showed an increase of CYP2E1 and CYP4A contents in both organs, but the increase was higher in liver than in kidney microsomes. Chemical inhibitions using CYP2E1 competitive inhibitors (such as chlorzoxazone and ethanol) led to a nonsignificant inhibition of the renal (omega-1)-hydroxylation of lauric acid. In contrast, 17-octadecynoic acid (a mechanism-based inhibitor of omega-hydroxylase) was able to inhibit both omega- and (omega-1)-hydroxylations of lauric acid in kidney microsomes. Immunoinhibitions specific to CYP2E1 significantly decreased the (omega-1)-hydroxylation of lauric acid in liver, but not in kidney microsomes, whereas the polyclonal anti-CYP4A1 antibody inhibited omega- and (omega-1)-hydroxylations of lauric acid in kidney microsomes. All of these results show that lauric acid hydroxylations in liver and kidney respond in different manners to ethanol treatment. Lauric acid (omega-1)-hydroxylation, a highly specific probe for CYP2E1 in rat and human liver microsomes, is mediated by a CYP4A isoform in rat kidney microsomes.

Animals↗
PubMed1995

Human skin permeability enhancement by lauric acid under equilibrium aqueous conditions.

An in vitro method was developed to investigate the enhancement of hydrocortisone transport across human stratum corneum (SC) by a model enhancer, lauric acid, in aqueous solutions under equilibrium conditions with respect to the enhancer. In contrast to classical (i.e., nonequilibrium) loading techniques, in which the enhancer is applied only to the donor side of SC either in pure form or in an organic solvent while enhancer-free aqueous buffers are placed in the receptor phase, this method allowed the investigation of pH effects, concentration effects, and reversibility of both enhancer uptake and enhancement of drug transport under thermodynamically well-defined conditions. The SC-buffer partition coefficients for lauric acid were linear with concentration and sigmoidal with pH, suggesting that both the neutral species and laurate anion partition into SC. Comparisons of partition coefficients in delipidized and untreated SC as a function of pH indicated that the uptake of lauric acid in neutral form is governed primarily by the lipid domain, whereas the protein domain accounts for anion uptake. The effects of lauric acid on skin permeability were > 80% reversible upon extraction of the enhancer from the membrane. However, the degree of enhancement of hydrocortisone permeability was nonlinearly dependent on the equilibrium concentration of lauric acid in either the aqueous buffer or the membrane, exhibiting thresholds in the appearance of enhancement with concentration. The enhancer concentration necessary to achieve isoenhancement of about 6-fold varied from approximately 1 x 10(-5) M at pH < pKa to approximately 1 x 10(-2) M at high pH (pH > 8) demonstrating the higher influence of the free acid species.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1990

Regiospecificity in the hydroxylation of lauric acid by rainbow trout hepatic cytochrome P450 isozymes.

The catalytic activity of two hepatic cytochrome P450 isozymes from untreated rainbow trout towards lauric acid was investigated. In a reconstituted system, cytochrome P450 LMC1 and P450 LMC2 were found to catalyze exclusively the omega- and (omega-1)-hydroxylation of lauric acid, respectively. Microsomal enzyme inhibition studies with polyclonal antibodies raised against the individual P450 isozymes showed that P450 LMC1 and LMC2, respectively, accounted for most if not all the omega- and (omega-1)-lauric acid hydroxylase activity of trout liver microsomes. The polyclonal antibodies were highly specific in that they only inhibited the enzyme activity of the P450 used as the immunogen. These results illustrate that as in mammals, omega- and (omega-1)-hydroxylation of lauric acid by trout liver microsomes can be carried out separately by distinct isozymes of cytochrome P450.

Animals↗
PubMedDate not supplied

Lauric acid as a model substrate for the simultaneous determination of cytochrome P450 2E1 and 4A in hepatic microsomes.

In vitro techniques have been utilized to investigate the microsomal enzymes involved in the metabolism of lauric acid and to establish conditions in which it can be used as a model substrate for both cytochrome P450 4A and cytochrome P450 2E1 in human liver microsomes. Studies of enzyme kinetics of lauric acid omega-hydroxylation in human liver microsomes indicated the involvement of more than one enzyme in this pathway, a relatively low Km enzyme with a Km of 22 microM +/- 12 (n = 8) and a high Km enzyme with a Km an order of magnitude higher (550 microM +/- 310, n = 7). The apparent Vmax for this component correlated with the rate of cyclosporin metabolism and was highly sensitive to ketoconazole inhibition. These results indicated that this enzyme was a member of the 3A subfamily. The activity associated with the low Km enzyme (P450 4A) did not correlate with P450 1A2, 2A6, 2C9/8, 2C19, 2D6, 2E1, or 3A activities in a bank of human liver microsomes and was not appreciably inhibited by ketoconazole, furafylline, quinidine, sulfaphenazole, or diethyldithiocarbamate (DDC). Lauric acid omega-1 hydroxylation demonstrated simple Michaelis-Menten kinetics in each of the human liver microsomal samples examined, with a Km of 130 microM +/- 42 (n = 8). This activity was highly correlated with chlorzoxazone 6-hydroxylation in human liver microsomes (r = 0.98, n = 14, p < 0.001) and was inhibited by both DDC and chlorzoxazone. Additionally, rats treated with the P450 2E1 inducer isoniazid demonstrated a 3-fold increase in lauric acid omega-1 hydroxylation relative to the control group. Thus, the lauric acid hydroxylation assay, at a substrate concentration of 20 microM, appears to be an effective and specific P450 model substrate capable of determining simultaneously P450 4A and P450 2E1 related activities in hepatic microsomal samples.

Animals↗
PubMed1989

Effect of hypolipidemic compounds on lauric acid hydroxylation and phase II enzymes.

Treatment of male Fischer 344 rats with various hypolipidemic drugs of different peroxisome proliferating potency (1-benzylimidazole, acetylsalicylic acid, clofibrate, tiadenol) led to an induction of liver lauric acid hydroxylase, whereas probucol, which is not a peroxisome proliferator, did not induce this enzyme. Activity of bilirubin UDP-glucuronosyltransferase was increased by all the compounds tested. The highest increase was observed after treatment with acetylsalicylic acid (2.3-fold). High correlation (r = 0.953) was observed between the activities of lauric acid hydroxylase and the corresponding activities of cytosolic epoxide hydrolase reported previously. The amount of microsomal epoxide hydrolase was not changed by any of the compounds. Whereas clofibrate and tiadenol decreased glutathione S-transferase activity with 1-chloro-2,4-dinitrobenzene as substrate, 1-benzylimidazole and probucol increased this activity. With 4-hydroxynonenal as a substrate qualitatively the same results were obtained with the exception that probucol did not affect the enzyme activity. When glutathione S-transferase activity was measured with cis-stilbene oxide as substrate only the more than five-fold increase after treatment with 1-benzylimidazole was significantly different from control values. Activity of dihydrodiol dehydrogenase was increased after treatment of rats with 1-benzylimidazole (1.5-fold), whereas application of tiadenol led to a decrease of enzyme activity. Feeding of male guinea pigs with clofibrate did not change the activity of peroxisomal beta-oxidation, cytosolic epoxide hydrolase or lauric acid hydroxylase. However, treatment with tiadenol caused an increase of these activities.

Animals↗
PubMed1988

Differential inactivation of plant lauric acid omega- and in-chain-hydroxylases by terminally unsaturated fatty acids.

The microsomal fraction from Vicia sativa L. cv. Septimane contains a cytochrome P-450-dependent lauric acid omega-hydroxylase that is inactivated in a time-dependent, pseudo-first-order manner when the microsomes are incubated with 11-dodecynoic acid. The rate constant for the inactivation is approximately 4.3-4.8 X 10(-3) s-1. In contrast, the olefinic analog 11-dodecenoic acid is primarily a time-independent inhibitor of the omega-hydroxylase. 1-Aminobenzotriazole, 3-phenoxy-1-propyne, and 3-(2,4-dichlorophenoxy)-1-propyne, mechanism-based inactivators of cinnamic acid 4-hydroxylase, and 9-decenoic acid, a mechanism-based inactivator of the lauric acid in-chain hydroxylase, are at best poor inactivators of the omega-hydroxylase. Conversely, cinnamic acid 4-hydroxylase is only slightly affected by concentrations of 11-dodecynoic acid that completely inactivate the omega-hydroxylase. 11-Dodecynoic acid is thus a potent, relatively specific, inactivator of the V. sativa lauric acid omega-hydroxylase.

Clofibrate↗
PubMed1997

Heme-coordinating analogs of lauric acid as inhibitors of fatty acid omega-hydroxylation.

A series of omega-substituted fatty acids with potential heme-coordinating groups was synthesized as inhibitors of lauric acid omega-hydroxylation. The compounds were evaluated using liver microsomes from clofibrate (CF)-induced rats and an engineered expressed CYP4A1-derived fusion protein called f4A1. omega-Imidazolyl-decanoic acid (compound 11) and omega-aminolauric acid (compound 7) were potent Type II ligands and potent inhibitors of lauric acid omega-hydroxylation in both CF-microsomes and f4A1. Replacing their terminal amino or imidazolyl groups with other potential iron-binding groups such as omega-methylsulfinyl-, omega-cyano-, omega-azido-, or omega-formamido all greatly reduced their potency as inhibitors of omega-hydroxylation and their affinity for cytochrome P450 as measured by Ks values. In CF-microsomes, inhibition of (omega-1)-hydroxylation of lauric acid by a homologous series of omega-imidazolyl-alkanoic acids varied only 2-fold but in the same incubations inhibition of omega-hydroxylation increased 22-fold upon going from C-8 to C-12. A similar dependence of binding affinity and inhibitory potency on chain length was also seen in the f4A1 system. In contrast, chain length had little effect on activity among n-alkylamines or N-alkylimidazoles lacking a carboxyl or other polar functional group, suggesting that 7, 11, and related bifunctional compounds interact with CYP4A1 in CF-microsomes and with f4A1 in a specific bidentate fashion. Imidazoles containing phenyl, benzyl, or phenylethyl substituents at N-1 interact less strongly than related N-alkyl-imidazoles of similar carbon number and hydrophobicity, suggesting that the steric bulk and/or rigidity of the phenyl ring is not well accommodated in the active site.

Animals↗