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PubMed1994

Relationship between cytochrome P450 2E1 and acetone catabolism in rats as studied with diallyl sulfide as an inhibitor.

Previous studies have demonstrated that cytochrome P450 2E1 (P450 2E1) catalyzes the oxidation of acetone in vitro. The present study was designed to determine the importance of P450 2E1 in the catabolism of acetone in rats using diallyl sulfide (DAS) as an inhibitor of this enzyme. After a single intragastric dose of DAS, blood samples were collected from rats at different time points, and blood acetone concentrations were measured by gas chromatography. In a low DAS dose (50 mg/kg body weight) group, the maximum acetone level of 6-fold higher than the normal level was reached at 6 hr; the acetone level returned to normal at 48 hr. In a high dose (200 mg/kg) group, the maximum acetone level of 9-fold higher than the normal level was reached at 12 hr; the acetone level returned to normal at 60 hr. The turnover time and fractional turnover rate of elevated acetone were 15.8 +/- 0.5 hr and 0.054 +/- 0.001 hr-1, respectively, for the low dose, and 19.2 +/- 0.6 hr and 0.046 +/- 0.005 hr-1, respectively, for the high dose. In a chronic experiment, DAS (50 and 200 mg/kg, i.g.) was given to rats daily for 29 days, and elevated blood acetone levels were observed during the entire experimental period: 2.0 to 2.8 micrograms/mL for the low dose and 3.4 to 3.9 micrograms/mL for the high dose at 24 hr after the 1st, 7th, 14th and 28th doses versus 0.8 to 0.9 micrograms/mL for the control. The increase of blood acetone level was closely related to the decreases of N-nitrosodimethylamine (NDMA) demethylase activity and P450 2E1 content in liver microsomes. Consistent with the lack of cumulative effect from the multiple doses of DAS on acetone level, rather stable levels of the DAS metabolites, diallyl sulfoxide (45.0 micrograms/mL, range: 33.8 to 58.6 micrograms/mL) and diallyl sulfone (11.7 micrograms/mL, range: 6.9 to 15.6 micrograms/mL), were observed at 24 hr after the 1st, 7th, 21st and 28th doses with DAS (200 mg/kg) in the chronic experiment. It is likely that the inactivation and inhibition of P450 2E1 by DAS and its metabolites block the oxidation of acetone and cause its elevation in blood. The results strongly suggest an important role of P450 2E1 in acetone catabolism under physiological conditions.

Acetone↗
PubMed1994

Characterization of human serum and umbilical artery semicarbazide-sensitive amine oxidase (SSAO). Species heterogeneity and stereoisomeric specificity.

Semicarbazide-sensitive amine oxidases (SSAOs) are located in cardiovascular smooth muscle, cartilage and brown adipose tissues of different species, including human. The enzyme is also present in blood, and its activity appears to be altered under certain pathological conditions. SSAOs from both human umbilical arteries and serum were partially purified, and some of their biochemical properties were investigated. Both human artery and blood SSAO exhibited very similar substrate preference, lack of stereospecificity catalyzing the deamination of pro-R and pro-S benzylamine-deuterated enantiomers, and were very sensitive towards (E)-2-(4-fluorophenethyl)-3-fluoroallylamine (MDL-72974A). It was concluded that circulating serum SSAO is identical to the SSAO from vascular tissues. Human SSAO exhibited distinctly different properties in comparison to bovine and rat SSAOs.

Allyl Compounds↗
PubMed1995

The chemopreventive agent diallyl sulfide. A structurally atypical phenobarbital-type inducer.

Diallyl sulfide (DAS), a known chemopreventive agent, was administered i.g. (200 or 500 mg/kg body wt/day) to male F344/NCr rats for 4 days. Livers were removed, and hepatic levels of a variety of drug-metabolizing enzymes were determined with either catalytic assays or by quantifying levels of total cellular RNA coding for the individual genes of interest. The high dose of DAS induced the cytochrome P450 (CYP) 2B subfamily to near maximal levels [i.e. similar to those induced by phenobarbital (PB)] and induced the CYP3A subfamily, while having minimal effects on the levels of the CYP1A subfamily. In addition, DAS induced the glutathione S-transferase alpha subfamily, the glutathione S-transferase mu subfamily, and epoxide hydrolase. Unlike PB, however, DAS was also able to induce quinone oxidoreductase. In fact, the pleiotropic hepatic response to DAS appeared to be similar to that elicited by PB, with the exception that only DAS induced quinone oxidoreductase. Finally, we determined that DAS induced the levels of a specific nuclear binding protein that appears to be associated with the induction of various genes that are part of the pleiotropic response caused by PB-type inducers.

Allyl Compounds↗
PubMed1976

Biochemical changes after hepatic injury by allyl alcohol and N-hydroxy-2-acetylaminofluorene.

Administration of hepatotoxic doses of allyl alcohol and N-hydroxy-2-acetylaminofluorene (N-OH-AAF) TO adult male rats produced periportal necrosis and functional derangement of the hepatic endoplasmic reticulum within 24 h. The rates of N-demethylation of ethylmorphine and p-hydroxylation of aniline were decreased 6 h following allyl alcohol administration, but cytochromes P-450 and b5 were unchanged. In contrast, administration of NOH-AAF decreased cytochromes P-450 and b5 and the rate of aniline p-hydroxylation, but did not change the rate of N-demethylation of ethylmorphine or the activities of cytochrome c reductase and glucose-6-phosphatase. No decrease was observed in the activity of the cytosol enzyme, DT diaphorase, following allyl alcohol treatment. The changes by these periportal hepatotoxins were compared with those produced both by central and midzonal hepatotoxins and with changes occurring in the liver after surgical partial hepatectomy.

Acetaminophen↗
PubMed1984

The protective action of glutathione on the microbial mutagenicity of the Z- and E-isomers of 1,3-dichloropropene.

The Z(cis)- and E(trans)-isomers of 1,3-dichloropropene (DCP), in confirmation of previous reports, caused dose-dependent increases in the numbers of reverse mutations in Salmonella typhimurium TA100 in the presence and absence of a 9000 X g supernatant fraction (S9) from the livers of Aroclor-treated rats. The relevance of these findings to mammals is uncertain, not least because of major differences in the metabolism of the DCPs in the microbial assay systems and in vivo. For example, (Z)-DCP is efficiently detoxified in mammals by the operation of a glutathione (GSH)-dependent S-alkyl transferase. It is possible that such detoxification could proceed only very slowly in the microbial assays because the concentrations of GSH could be severely rate-limiting even in those assays fortified by the addition of S9. The results obtained in the current study demonstrate a dramatic reduction in the microbial mutagenicity of both (Z)- and (E)-DCP when the concentration of GSH in the microbial assays was adjusted to a normal physiological concentration (5 mM). However, this protective action of GSH was at least as effective in the absence of S9 as in its presence, suggesting that it was not mediated by mammalian GSH transferase. There appears to be little or no GSH alkyl or aryl transferase in the cytosol of S. typhimurium TA100, but intracellular GSH is present at a concentration similar to that found in mammalian cells. Since the uncatalysed reaction between the DCPs and glutathione is relatively slow, the effect is not due simply to their destruction by GSH. It is possible that a physiological concentration of extracellular GSH maintains the intracellular GSH in a reduced form in which its nucleophilic thiol group competes effectively with the nucleophilic centres in the bacterial DNA for the haloalkenes. The current results highlight the efficiency of GSH-linked systems in affording protection against the genotoxic action of the DCPs. It may be presumed that their operation would exert a major limiting effect on the genotoxicity of (Z)- and (E)-DCP in mammals.

Allyl Compounds↗
PubMed1987

Microbial mutagenicity studies with (Z)-1,3-dichloropropene.

This study has confirmed that the direct mutagenicity previously observed when S. typhimurium TA100 was treated with (Z)-1,3-dichloropropene (DCP) was in fact due to trace impurities. These impurities result from autoxidation of (Z)-1,3-DCP and have now been identified. Both (Z)- and (E)-2-chloro-3-(chloromethyl)oxiranes (DCP oxides) were identified as significant products during this autoxidation. The mutagenic impurities formed by autoxidation were completely removed by adsorption chromatography on silicic acid. (Z)-1,3-DCP purified in this way had no direct-acting mutagenicity towards S. typhimurium TA100. However, (Z)-1,3-DCP undergoes mono-oxygenase-catalysed conversion into bacterial mutagens in the presence of S9 fraction or washed microsomes from rat liver. The glutathione-linked conjugation systems of mammalian tissues provided efficient protection against this indirect mutagenic action. However, the low concentration of glutathione in standard bacterial mutagenicity assays limits the glutathione S-alkyl transferase-catalysed detoxification of (Z)-1,3-DCP and its primary bioactivation product(s). When the concentration of glutathione was adjusted to the normal physiological concentration, the mono-oxygenase-dependent mutagenic action of (Z)-1,3-DCP was virtually eliminated. These results therefore are consistent with the view that bacterial mutation assays are only qualitative indicators of potential mammalian genotoxicity.

Allyl Compounds↗
PubMed1996

A pharmacokinetic model of anaerobic in vitro carbon tetrachloride metabolism.

Carbon tetrachloride (CCl4) is a potent hepatotoxic agent whose toxicity is mediated through cytochome P450-dependent metabolism. Results from anaerobic in vitro experiments with hepatic microsomes isolated from male F-344 rats indicate that chlorofom (CHCl3) formation from CCl4 is nonlinear with dose. Dose is traditionally expressed as the amount of CCl4 added to the vial. In this study, a pharmacokinetic model has been developed to calculate the concentration of CCl4 in the microsomal suspension. Hepatic microsomes prepared from fed and fasted animals were incubated with CCl4 under anaerobic conditions and formation of CHCl3 over a 5-min incubation period was monitored by headspace gas chromatography. Dose-response curves, based on total amount of CCl4 added to the microsomes, revealed a nonlinear, biphasic appearance of CHCl3, with fasting slightly increasing CHCl3 production in microsomes prepared from fasted rats. Microsomes were also pretreated with the CYP2E1 inhibitor, diallyl sulfone (DAS), before addition of CCl4. In uninhibited microsomes, there appeared to be a high-affinity saturable phase of metabolism occurring at lower concentrations followed by a linear phase at higher CCl4 concentrations. Following DAS pretreatment, the saturable portion of the dose-response curve was inhibited more than the linear phase with the biphasic CHCl3 production becoming more linear. DAS inhibition eliminated the effect of fasting on CHCl3 formation. The best fit kinetic constants for the saturable phase resulted in an estimate of V(max) of 0.017 mg/h/mg protein (V(maxc) = 7.61 mg/h/kg) and Km of 2.3 mg/l (15 microM). The linear phase rate constant (kf) was determined to be 0.046 h-1) (kfc = 0.03 h-1). In conclusion, a pharmacokinetic model has been developed for anaerobic in vitro metabolism of CCl4 to CHCl3 that estimates metabolic rates based on CHCl3 formation and actual CCl4 concentration in the microsomal suspension.

Allyl Compounds↗
PubMed1975

Effect of essential oil of onion (allyl propyl disulphide) on blood glucose, free fatty acid and insulin levels of normal subjects.

The administration of allyl propyl disulphide (APDS), a volatile substance contained in onion, to six normal volunteers after a 12 hour fast caused a significant fall in the blood glucose levels and a significant rise in the serum insulin levels during the subsequent 4 hours. It is argued that this effect is due to an insulin sparing action. The expected rise of serum free fatty acid levels after fasting did not occur after APDS administration and this effect is probably related to the simultaneous rise in the insulin levels.

Allyl Compounds↗
PubMed1995

Pharmacokinetics and pharmacodynamics of the monoamine oxidase B inhibitor mofegiline assessed during a phase I dose tolerance trial.

The safety, pharmacokinetics, and pharmacodynamics of single oral doses of up to 48 mg and daily (for 28 days) doses of up 24 mg mofegiline were investigated in healthy male volunteers. Plasma pharmacokinetics indicated rapid absorption and elimination: time to reach maximum concentration occurred at about 1 hour; half-life ranged from 1 to 3 hours. Maximal plasma concentration and area under the plasma concentration-time curve increased and oral clearance decreased disproportionately with dose. Mofegiline rapidly and markedly inhibited platelet monoamine oxidase B (MAOB) activity, which returned to baseline within 14 days. Urinary excretion of phenylethylamine increased proportionately with doses up to 24 mg. No changes in urinary elimination of catecholamines, blood pressure, heart rate, or ECG were observed. A classic maximum tolerated dose was not achieved in these studies. However, the 48 mg single dose and the 24 mg multiple daily dose far exceeded the dose (1 mg) that was associated with > 90% platelet MAOB inhibition.

Administration, Oral↗
PubMed1986

Spermicidal effect in vitro by the active principle of garlic.

The in vitro spermicidal effect of Allitridum, an active principle of garlic, was investigated. The data showed that sperm motility was inhibited with various concentrations of Allitridum at different intervals ranging from 20 seconds-200 minutes as compared to control. An obvious immobilization of spermatozoa occurred at 7.5 mg/ml of Allitridum. The effects on sperm motility appeared to be dose-dependent.

Allyl Compounds↗