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Biomedical subjects

A M Butler

Publications and source records attributed to A M Butler.

At least 19 recordsLinked to original sources
PubMed1998

Comparative induction of CYP3A and CYP2B in rat liver by 3-benzoylpyridine and metyrapone.

3-Benzoylpyridine (3BP) is a major metabolite of HGG-12, and oxime that has been synthesized as a potential antidote to the toxic effects of soman and other anticholinesterases. Structural similarities exist between 3BP, the cytochrome P450 (CYP)-inducer metyrapone (MET) and other 3-substituted pyridines that interact with CYPs. The present study evaluated the regulatory effects of 3BP on CYP expression in rat liver. Both 3BP and MET (100 mg/kg) increased total hepatic microsomal holo-CYP content significantly 24 h after administration to male rats. Pronounced increases in activities mediated by CYP2B (androstenedione 16 beta-hydroxylation and 7-pentylresorufin O-depentylation) were produced by 3BP and MET, which correlated with respective 9- and 14-fold increases in CYP2B immunoreactive protein. In addition, both agents slightly increased rates of microsomal CYP3A-dependent steroid 6 beta-hydroxylation, troleandomycin metabolite complex formation and total CYP3A immunoreactive protein. Induction of the dexamethasone-inducible CYP3A23 mRNA to 4.5- and 2.5-fold of control was detected in liver of MET- and 3BP-induced rats; CYP3A2 mRNA levels were unchanged. Analogous in vitro studies revealed that MET was a preferential inhibitor of CYP3A-mediated steroid 6 beta-hydroxylation activity, but 3BP was inactive against constitutive steroid hydroxylase CYPs. These findings indicate that the structurally related 3BP and MET elicit similar induction effects on CYPs 2B and 3A23 in rat liver after in vivo administration, but differential inhibitory effects of the chemicals on CYP activity in vitro. Recent reports have implicated a microsomal binding site in the induction of CYP3A1/3A23 in rat liver. In light of the present findings, substituted pyridines like 3BP may be useful tools in structure-activity studies to evaluate the physicochemical requirements for binding to this protein.

Androstenedione↗
PubMed1997

Induction of cytochromes P450 2B and 2E1 in rat liver by isomeric picoline N-oxides.

Pyridine derivatives are widely used solvents and precursors for the synthesis of chemicals of industrial importance. Oxidized metabolites have been implicated in the observed toxicity of pyridines and are known to induce drug-metabolizing enzymes in rat liver. In this study the three isomeric picoline (methylpyridine) N-oxides, as major oxidized metabolites of 2-, 3- and 4-picoline, were evaluated as inducers of cytochrome P450 (CYP) enzymes in rat liver. After a single dose of 100 mg/kg 24 h before sacrifice the 3- and 4-isomers were effective inducers of microsomal substrate oxidations associated with the phenobarbital-inducible CYPs 2B; upregulation of CYP2B protein was confirmed by immunoblotting. In contrast, the 2-isomer did not increase CYP2B protein or activity in rat liver but CYP2E1 protein expression was upregulated by the isomers to 160-200% of control. The three chemicals increased aniline 4-hydroxylation activity in rat liver, which is consistent with induction of CYPs 2B or 2E1 and 4-nitrophenol 2-hydroxylation activity was increased in microsomal fractions from 3- and 4-picoline N-oxide-treated rats. The activities of several other CYPs were also determined and CYP1A-dependent 7-ethylresorufin O-deethylation was increased (to approximately 6- and 2-fold of control) by the 3- and 4-isomer, respectively, whereas the activity of CYP3A-mediated androstenedione 6beta-hydroxylation was decreased by the agents--most notably by the 2-isomer. During NADPH-supported oxidation of CCl4, lipid peroxidation was increased in microsomes from 3- and 4-picoline N-oxide-pretreated rats and was modulated in vitro by the CYP2B inhibitor orphenadrine, but not by the CYP2E1 inhibitor 4-methylpyrazole. These findings establish that particular isomers of picoline N-oxide rapidly upregulate CYP2B or, to a lesser extent, CYP2E1 and implicate CYP2B in the enhanced lipid peroxidation observed in microsomes from rats treated with 3- and 4-picoline N-oxides. Such induction process may contribute to the hepatotoxicity of pyridines by enhancing the capacity for microsomal lipid peroxidation.

Animals↗
PubMed1997

Biotransformation of parathion in human liver: participation of CYP3A4 and its inactivation during microsomal parathion oxidation.

Studies in rat liver have shown that cytochrome P450 (CYP) enzymes mediate the oxidative biotransformation of the phosphorothioate pesticide parathion to paraoxon and 4-nitrophenol. Transfer of the phosphorothioate thionosulfur atom to the CYP apoprotein results in amino acid modification and enzyme inactivation. Our study investigated the role of human hepatic CYP in parathion oxidation and their relative susceptibilities to inhibition and inactivation. Rates of parathion oxidation varied about 10-fold in microsomes from 23 individual livers (1.72-18.33 nmol total metabolites/mg protein/min). Linear regression of rates of parathion oxidation with those of other microsomal CYP reactions implicated CYP3A4 in the reaction. Thus, parathion oxidation was correlated strongly with testosterone 6beta-hydroxylation (r2 = 0.95, n = 11), but not with activities mediated by CYP 1A2, 2C9 or 2E1. CYP 3A4 expressed in lymphoblastoid cell lines was an efficient catalyst of parathion oxidation, although CYP 1A2 and 2B6 also catalyzed the activity. The CYP3A4 inhibitors ketoconazole and triacetyloleandomycin decreased the observed rate of microsomal parathion oxidation, but chemicals known to interact preferentially with other human CYP were essentially noninhibitory. P450 was lost during parathion biotransformation in human hepatic microsomes. Thus, incubation (10 min) of parathion (25 microM) with NADPH-supplemented microsomes led to an apparent 19 +/- 4% decrease in holo-P450 content. Several CYP-specific oxidation reactions were inhibited and inactivated by parathion. Testosterone 6beta-hydroxylation (mediated by CYP3A4), 7-ethylresorufin O-deethylation (CYP1A2) and tolbutamide methyl hydroxylation (CYP2C9/10), but not aniline 4-hydroxylation (CYP2E1), were inhibited effectively by parathion. Preincubation of microsomes with parathion and NADPH intensified the extent of inhibition (i.e., elicited inactivation) of reactions mediated by 3A4 and 1A2 and, to a lesser extent, 2C9. In summary, these findings strongly implicate CYP 3A4 as the principal catalyst of parathion oxidation in human liver, although other CYP may play a lesser role. During parathion oxidation CYP3A4 undergoes significant inactivation. In view of the role of this enzyme in the oxidation of many therapeutic agents, exposure to phosphorothioate pesticides may adversely affect drug elimination in humans.

Aniline Hydroxylase↗
PubMed1997

Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites.

The antihypertensive agent diltiazem (DTZ) impairs hepatic drug metabolism by inhibition of cytochrome P450 (CYP). The accumulation of DTZ metabolites in serum occurs during prolonged therapy and leads to decreased DTZ elimination. Thus, DTZ metabolites may contribute to CYP inhibition. This study assessed the role of human CYPs in microsomal DTZ oxidation and the capacity of DTZ metabolites to inhibit specific CYP activities. DTZ N-demethylation varied 10-fold in microsomal fractions from 17 livers (0.33-3.31 nmol/mg of protein/min). DTZ oxidation was correlated with testosterone 6beta-hydroxylation (r = 0.82) and, to a lesser extent, tolbutamide hydroxylation (r = 0.59) but not with activities mediated by CYP1A2 or CYP2E1. CYP3A4 in lymphoblastoid cell microsomes catalyzed DTZ N-demethylation but CYP2C8 and CYP2C9 were also active (approximately 20% and 10% of the activity supported by CYP3A4); seven other CYPs produced little or no N-desmethyl DTZ from DTZ. The CYP3A4 inhibitors ketoconazole and troleandomycin decreased microsomal DTZ oxidation, but inhibitors or substrates of CYP2C, CYP2D and CYP2E1 produced no inhibition. Some inhibition was produced by alpha-naphthoflavone, a chemical that inhibits CYP1As and also interacts with CYP3A4. In further experiments, the capacities of DTZ and three metabolites to modulate human CYP 1A2, 2E1, 2C9 and 3A4 activities were evaluated in vitro. DTZ and its N-desmethyl and N,N-didesmethyl metabolites selectively inhibited CYP3A4 activity, whereas O-desmethyl DTZ was not inhibitory. The IC50 value of DTZ against CYP3A4-mediated testosterone 6beta-hydroxylation (substrate concentration, 50 microM) was 120 microM. The N-desmethyl (IC50 = 11 microM) and N,N-didesmethyl (IC50 = 0.6 microM) metabolites were 11 and 200 times, respectively, more potent. From kinetic studies, N-desmethyl DTZ and N,N-didesmethyl DTZ were potent competitive inhibitors of CYP3A4 (Ki = approximately 2 and 0.1 microM, respectively). CYP3A4 inhibition was enhanced when DTZ and N-desmethyl DTZ underwent biotransformation in NADPH-supplemented hepatic microsomes in vitro, supporting the contention that inhibitory metabolites may be generated in situ. These findings suggest that N-demethylated metabolites of DTZ may contribute to CYP3A4 inhibition in vivo, especially under conditions in which N-desmethyl DTZ accumulates, such as during prolonged DTZ therapy.

Biotransformation↗
PubMed1996

Restoration of cytochrome P450 2C11 in vitamin A-deficient rat liver by exogenous androgen.

Down-regulation of microsomal androgen-dependent CYP2C11 is produced in male rat liver by dietary vitamin A deficiency. Decreased circulating androgen concentrations also occur in vitamin A-deficient male rats. Both effects are prevented by addition of all-trans-retinoic acid to the diet. The present study evaluated directly whether androgen deficiency may be responsible for the down-regulation of 2C11 in vitamin A-deficient male rats. The major finding was that subcutaneous administration of the androgen methyltrienolone (MT) during the final week of the study restored CYP2C11 protein and its associated steroid 16alpha-hydroxylation activities to control levels; CYP2C11 mRNA was also restored. Despite the efficient restoration of CYP2C11 at a pretranslational level, no alteration in vitamin A status was apparent and animals remained vitamin A deficient after MT treatment. The possibility was assessed that vitamin A can maintain the microsomal content of CYP2C11 in normal liver. However, in contrast to MT, administration of ATRA to gonadectomized male rats did not restore 2C11 in liver. These findings establish that the major effect of vitamin A deficiency on CYP2C11 in male rat liver is mediated indirectly by androgen deficiency.

Androstenedione↗
PubMed1996

Enhanced inhibition of microsomal cytochrome P450 3A2 in rat liver during diltiazem biotransformation.

Pharmacokinetic drug interactions involving the calcium channel blocker diltiazem (DTZ) have been attributed to inhibition of microsomal cytochrome P450 (P450)-mediated drug oxidation. Accumulation of certain DTZ metabolites during dosage with the drug, as well as dose-related differences in DTZ pharmacokinetics, suggests that DTZ metabolites may also participate in P450 inhibition. The present study evaluated a series of putative DTZ metabolites as inhibitors of major constitutive P450s in rat liver in vitro, in relation to DTZ biotransformation. The principal finding to emerge was that the N-demethylated metabolite of DTZ was a more potent competitive inhibitor than DTZ of CYP3A2-dependent testosterone 6 beta-hydroxylation. This P450 appeared to be the preferred target for inhibition, because the observed K/K(m) ratio for inhibition of CYP3A2-dependent steroid hydroxylation was approximately 4- and 100-fold lower than those for CYP2C11 and CYP2A1-dependent pathways, respectively. It was also established that N-desmethyl-DTZ was a major metabolite formed during microsomal DTZ biotransformation in rat liver in vitro. The other primary metabolites, desacetyl-DTZ and O-desmethyl-DTZ, were ineffective inhibitors of any pathways of steroid oxidation by P450s, but several other potential metabolites, which were not detected in microsomal incubations, also inhibited P450 activity. Consistent with previous reports, there was no evidence of P450 inactivation or complexation by DTZ, but the drug and its N-desmethyl metabolite generated binding interactions with ferric P450 in rat hepatic microsomes. Considered together, the findings of the present study establish that N-desmethyl-DTZ is a preferential inhibitor of CYP3A2 in rat hepatic microsomes, with greater potency than the parent drug. This is consistent with clinical reports in which this metabolite accumulates during multiple-dose therapy with DTZ. The competitive nature of the inhibitory interaction suggests that the eventual elimination of N-desmethyl-DTZ should restore normal hepatic oxidation capacity.

Animals↗
PubMed1995

Pretranslational down-regulation of cytochromes P450 2C11 and 3A2 in male rat liver by tumor necrosis factor alpha.

BACKGROUND & AIMS: The cytokine tumor necrosis factor alpha (TNF-alpha) is a primary inflammatory mediator after liver injury. Several cytokines impair the regulation of cytochrome P450 (CYP) genes in liver, but the specificity of these effects remains unclear. This study investigated the effects of recombinant murine TNF-alpha on the expression of specific constitutive CYPs in male rat liver. METHODS: Microsomal steroid hydroxylation was used to indicate the activities of specific CYPs after TNF-alpha treatment and immunoblotting to correlate CYP activities with protein contents. CYP messenger RNA levels were measured by solution hybridization. RESULTS: Testosterone 2 alpha/16 alpha- and 6 beta-hydroxylations, mediated respectively by CYPs 2C11 and 3A2, were decreased after TNF-alpha treatment, whereas 7 alpha-hydroxylation (CYP 2A1) was unchanged. Similarly, progesterone 2 alpha/16 alpha- (CYP 2C11) and 6 beta-hydroxylations (CYP 3A2), but not 21-hydroxylation (CYP 2C6), were decreased after TNF-alpha treatment. 2C11 and 3A2 apoproteins and messenger RNAs, but not 2A1 apoprotein, were decreased after TNF-alpha treatment; changes in messenger RNAs were evident 4 hours after treatment. CONCLUSIONS: TNF-alpha down-regulates CYPs 2C11 and 3A2 in male rat liver at a pretranslational level, whereas two other constitutive CYPs, 2A1 and 2C6, seem refractory to TNF-alpha. Thus, impaired CYP regulation by TNF-alpha resembles the combined effects of autologous interferons (on 3A2) and interleukins (on 2C11).

Analysis of Variance↗
PubMed1995

Pretranslational down regulation of cytochrome P450 2C11 in vitamin A-deficient male rat liver: prevention by dietary inclusion of retinoic acid.

Manipulation of vitamin A intake has been associated with altered rates of cytochrome P450 (P450)-mediated microsomal drug oxidation. Dietary vitamin A deficiency reportedly results in decreased rates of P450-dependent substrate oxidation, but the mechanisms underlying these changes remain unclear. In this study, the effects of dietary vitamin A modulation, as well as dietary inclusion of all-trans-retinoic acid (ATRA), on major constitutive P450s were defined. Total microsomal P450 in deficient male rats was decreased to 72% of control (0.63 +/- 0.07 vs. 0.88 +/- 0.08 nmol/mg of protein; P < .05); this was prevented by inclusion of ATRA (12 micrograms/g) in the deficient diet. Dietary vitamin A deficiency decreased rates of P450 2C11-mediated testosterone 2 alpha- and 16 alpha-hydroxylation in rat liver to 44 and 47% of respective adequate control, whereas rates of 6 beta- and 7 alpha-hydroxylation of the steroid were unaltered; inclusion of ATRA into the deficient diet prevented the loss of 2C11 activities. Immunoblot and RNA analysis revealed decreases in P450 2C11 apoprotein and its corresponding mRNA in liver from deficient rats that was prevented by inclusion of ATRA in the deficient diet. Serum testosterone concentrations were reduced in deficient rats and this also was prevented by dietary ATRA. To discern whether this was a direct effect of vitamin A on P450 2C11 regulation, further experiments evaluated the effect of ATRA administration to male rats maintained on standard rat chow (vitamin A-adequate). Dose- and time-dependent decreases in P450 2C11 activity were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Identification of a reversible component in the in vitro inhibition of rat hepatic cytochrome P450 2B1 by parathion.

Cytochrome P450 (P450) enzymes are inactivated in suicidal fashion during microsomal parathion oxidation. In the present study, two distinct components of the inhibition of the phenobarbital (PB)-inducible P450 2B1 by parathion were characterized. Here we report for the first time that low concentrations of parathion potently and reversibly inhibited, but did not inactivate, 2B1. In contrast, the previously described inactivation process occurred only at considerably higher parathion concentrations, at which concentrations enzyme activity was already extensively inhibited. At low concentration, parathion was a competitive inhibitor of 2B1-mediated androstenedione 16 beta-hydroxylation (Ki = 0.44 +/- 0.07 microM) and of 7-pentylresorufin O-depentylation (Ki = 0.40 +/- 0.03 microM) in microsomes from PB-pretreated rats and was similarly effective against androstenedione 16 alpha- and 16 beta-hydroxylation catalyzed by purified 2B1. Although preincubation of higher concentrations of parathion (> 5 microM) with NADPH-supplemented microsomes from PB-pretreated rat liver decreased holo-P450, heme loss was not observed near the Ki values. Instead, half-maximal loss of P450 occurred at 6 microM and at 9 microM parathion in PB-pretreated microsomes and in the reconstituted system, respectively. Parathion metabolism was efficient in PB-microsomes (Km values for 4-nitrophenol and paraoxon formation were 13 microM and 10 microM, respectively) and in the reconstituted system (corresponding Km values were 19 microM and 14 microM). Thus the constants for P450 inactivation and for parathion metabolism were similar and were at least 15-fold greater than the Ki values for the reversible process.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Inhibition of microsomal 17 beta-hydroxysteroid oxidoreduction activities in rat liver by all-trans-, 9-cis- and 13-cis-retinoic acid.

Retinoids and steroid hormones mediate their biological effects through nuclear receptors. However, retinoids may alter the intracellular availability of ligands for steroid receptor activation by modulating the activity of biotransformation enzymes. This study investigated the modulation of NAD(H)-linked steroid oxidoreductases in rat hepatic microsomes by retinoids. 13-cis-Retinoic acid inhibited testosterone 17 beta-dehydrogenation (Ki 2.4 +/- 0.5 microM; Km/Ki ratio 0.34 +/- 0.06) but androstenedione reduction was less susceptible to inhibition (Ki 27 +/- 13 microM; Km/Ki ratio 0.045 +/- 0.12). All-trans-retinoic acid was less potent than the 13-cis-isomer and 9-cis-retinoic acid was of intermediate potency. In vivo administration of all-trans-retinoic acid (60 mg/kg i.p. for 7 days) decreased hepatic microsomal oxidoreduction activity, but exposure over shorter periods and 13-cis-retinoic acid were without effect. Thus, all-trans-retinoic acid elicits direct inhibition and may also alter the normal regulation of the oxidoreductase under certain conditions. Three geometric isomers of retinal were potent inhibitors of testosterone dehydrogenation (IC50s approximately 6 microM), but were ineffective against androstenedione reduction. These findings suggest that certain anti-hormonal effects of retinoids may be attributable in part to modulation of endobiotic biotransformation prior to receptor binding and activation.

17-Hydroxysteroid Dehydrogenases↗
PubMed1994

Competitive inhibition of human liver microsomal cytochrome P450 3A-dependent steroid 6 beta-hydroxylation activity by cyclophosphamide and ifosfamide in vitro.

The prodrugs cyclophosphamide (CP) and ifosfamide (IF) are oxidized by hepatic cytochrome P450 (P450) to the active cytotoxic species, phosphoramide mustard. Acrolein (prop-2-enal) is also formed during CP and IF activation in rat liver and has been associated with P450 destruction. Analogous inactivation of human liver P450s by CP or IF could lead to pharmacokinetic interactions with coadministered drugs. The present study investigated the susceptibilities of human hepatic P450s to inhibition and inactivation by CP and IF in vitro. Unlike the situation in rat liver microsomes, total P450 was not decreased after incubation of CP or IF with NADPH and human fractions. However, CP and IF inhibited testosterone 6 beta-hydroxylation mediated by P450s 3A but not P450 1A2-dependent 7-ethylresorufin O-deethylation, P450 2C-dependent tolbutamide methyl hydroxylation or P450 2E1-mediated N-nitrosodimethylamine N-demethylation. Kinetic analysis indicated that the drugs were reversible (competitive) inhibitors of testosterone 6 beta-hydroxylation (Km, 94 +/- 8 microM) in human liver microsomes (KiS, 510 +/- 20 microM and 490 +/- 40 microM for CP and IF, respectively). Time-dependent intensification of the inhibition of the activity by CP or IF did not occur; this supports the observation that P450 was refractory to inactivation. The rates of acrolein formation from CP and IF in human hepatic microsomes (0.76 +/- 0.23 and 0.19 +/- 0.07 nmol min-1 mg-1 of protein, respectively) were only 18% and 10% of the rates estimated in fractions from untreated rat liver (4.20 +/- 0.04 and 1.96 +/- 0.12 nmol min-1 mg-1 of protein, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Acrolein↗
PubMed1993

Inhibition and inactivation of constitutive cytochromes P450 in rat liver by parathion.

Phosphorothioate pesticides, such as parathion (O,O-diethyl-O-4-nitrophenyl phosphorothioate), undergo enzymic oxidation to the active insecticidal agents that are the analogous organophosphorus compounds. In hepatic microsomal fractions, the NADPH-mediated conversion of parathion to paraoxon occurs with concomitant loss of cytochrome P450 (P450) and associated activities. In this study, the capacity of parathion to inactivate specific P450 enzymes was studied in rat hepatic microsomes. Parathion was a potent inhibitor of P450 3A2- and 2C11-mediated androst-4-ene-3,17-dione (androstenedione) 6 beta- and 16 alpha-hydroxylation (Ki values of 13 +/- 2 and 2.3 +/- 0.1 microM, respectively, and Km/Ki ratios of 1.4 +/- 0.2 and 11 +/- 1, respectively). After a 10-min preincubation between parathion and NADPH-supplemented microsomes, to inactivate P450 before androstenedione hydroxylation was carried out, the corresponding Km/Ki ratios were increased to 3.5 +/- 0.4 and 35 +/- 6, reflecting 2.5- and 3.2-fold enhancement of inhibition of P450 3A2- and 2C11-dependent activities. In contrast to these findings, P450 2A1/2-mediated androstenedione 7 alpha-hydroxylation was refractory to inhibition and P450 2C6-mediated progesterone 21-hydroxylation was inhibited but not inactivated by the pesticide. Further studies established that androstenedione 6 beta- and 16 alpha-hydroxylation pathways were inactivated with maximal half-times of 2.59 min and 1.72 min, respectively. Although the incubation of parathion (50 microM) with rat liver microsomes for 10 min led to a 16% decrease in P450 estimated spectrophotometrically, immunoblot analysis revealed no change in the microsomal content of P450 2C11 apoprotein. Finally, NADPH-mediated metabolism of parathion to paraoxon (by desulfuration) and 4-nitrophenol (by oxidative cleavage of the phosphorothioate ester) occurred efficiently in microsomes (4.32 and 4.35 nmol/min/mg of protein, respectively). P450 loss was estimated under the same incubation conditions and, thus, 210 parathion molecules were oxidized for each molecule of holo-P450 lost. These findings establish that parathion is a potent inhibitor and inactivator of the principal constitutive P450s, 3A2 and 2C11, in rat liver, whereas the P450s 2A1 and 2A2 are refractory to either inhibition or inactivation. Another major constitutive enzyme, P450 2C6, is inhibited effectively by parathion but does not appear to be subject to inactivation.

Androstenedione↗
PubMed1987

Social drinking and cognitive functioning in college students: a replication and reversibility study.

The purposes of this study were to replicate a previous study of the relationship between alcohol consumption and cognitive functioning in college students and to investigate the reversibility of negative effects of social drinking on cognitive functioning when randomly assigned subjects abstained from drinking for 2 weeks. The previous study was replicated by administering the same battery of neuropsychological tests to 170 subjects (103 women) during the first testing session. Like the original study, the present study demonstrated several significant predicted inverse relationships between drinking and cognitive performance, but specific relationships between various drinking and cognitive variables were not replicated. As in the original study, some significant nonpredicted relationships also occurred. At the end of the first testing session, subjects were randomly assigned either to abstain from drinking or to maintain their usual drinking patterns for 2 weeks. They were then administered a different neuropsychological battery designed to assess functions similar to the original battery. Consumption the previous 2 weeks was significantly lower in the abstain group than in the maintain group, but there were no significant differences in the predicted direction between groups on the cognitive variables. Several significant predicted inverse correlations between drinking variables and cognitive performance occurred, but some nonpredicted relationships occurred also. Problems and implications for research in social drinking are discussed.

Adult↗
PubMed1985

Alcohol use and cognitive functioning in men and women college students.

Two studies of the relationship between alcohol consumption and cognitive functioning in men and women college students are presented. Study 1 showed several predicted relationships of decreased cognitive performance on various tests with increased quantity of alcohol per occasion and total lifetime consumption in both women and men. Study 2a was designed to replicate study 1, but the pattern of relationship of cognitive and consumption variables was quite different, e.g., increased cognitive performance was associated with increased quantity per occasion for several tests in males. Study 2b was designed to demonstrate reversibility of the negative effects of consumption on cognition by randomly assigning half of the subjects to abstain for two weeks. Reversibility was not demonstrated. Difficulties in studying these effects in college students are discussed.

Adult↗
PubMed1983

The influence of amines on various platelet responses.

Four amines, galactosamine, mannosamine, histamine and arginine were studied for their effects on platelet aggregation, platelet morphological changes, platelet protein phosphorylation and platelet secretion. Galactosamine inhibited platelet aggregation in response to arachidonic acid and ionophore A23187 but did not inhibit changes in platelet morphology, or in platelet protein phosphorylation in response to these agents and only partially inhibited platelet secretion. The results suggest that galactosamine can be used as a selective inhibitor of platelet-platelet attachment without having a significant effect on intracellular processes. Mannosamine was similar to galactosamine except that it partially suppressed phosphorylation of myosin light chain. Histamine was similar to mannosamine except that some platelet damage was seen in platelets exposed to histamine and arachidonic acid or ionophore A23187. Arginine was non-selective: it suppressed platelet aggregation, secretion and phosphorylation of myosin light chain and a 40 kDa protein (40P) in response to arachidonic acid and ionophore A23187. Arginine was also potent in suppressing platelet morphological changes. When the same four amines were evaluated for their effects on thrombin-induced aggregation; secretion was inhibited concomitantly with inhibition of aggregation. Inhibition of myosin light chain and 40P phosphorylation was evident with galactosamine, suggesting that when thrombin is used as the agonist, galactosamine is not a specific inhibitor of platelet-platelet attachment. These amines therefore have various effects on platelet responses. Under some conditions and with arachidonic acid or ionophore A23187 as agonist, one of them, galactosamine, can be used as a selective inhibitor of platelet-platelet attachment.

Arachidonic Acid↗
PubMed1983

Alcohol consumption and cognitive functioning in college students.

Decreased cognitive performance was significantly correlated with increased quantity of alcohol per occasion and with total lifetime consumption in both women and men college students tested while sober. In men, however, increased performance on some tasks was also significantly correlated with increased frequency of drinking.

Adult↗