Enhancement of alcohol-induced hypoglycaemia by H2-receptor antagonists.

The oral ethanol loading test (0.5 g/kg body mass) was carried out in 3 groups with 10 healthy male volunteers each before and after 7 days of administration of either cimetidine (CAS 51481-61-9), ranitidine (CAS 66357-59-3), or famotidine (CAS 76824-35-6). The parameters determined during 6 h comprised the blood levels of ethanol, acetaldehyde, glucose, lactate, pyruvate and bicarbonates, as well as blood pH, PCO2 and PO2. Only ranitidine significantly increased the mean blood ethanol concentration and none of the drugs modified the blood acetaldehyde concentration. Hypoglycaemia following alcohol ingestion was significantly enhanced by all H2-receptor antagonists, but was most pronounced after famotidine. The alcohol-induced rise in blood pyruvate and lactate rather had a tendency to decrease during the second test. The presented results suggest that the evident enhancement of alcohol-induced hypoglycaemia by H2-receptor antagonists is not dependent on the increase of ethanol absorption from the gastrointestinal tract, but represents rather a specific effect of these drugs on glucose metabolism.

Alcohol tolerance in patients with non-insulin-dependent (type 2) diabetes treated with sulphonylurea derivatives.

The oral ethanol loading test (0.5 g/kg body mass given as 40% solution) was carried out in 5 groups, each of 10 out-patients with non-insulin-dependent (type 2) diabetes before and after 10 days of treatment with one of the following sulphonylurea derivatives: tolbutamide (CAS 64-77-7) 0.5 t.i.d., chlorpropamide (CAS 94-20-2) 0.5 once daily morning, glibornuride (CAS 26944-48-9) 0.025 t.i.d., glibenclamide (CAS 10238-21-8) 0.005 t.i.d. and glipizide (CAS 29094-61-9) 0.005 t.i.d. The response to alcohol (facial flush, heart rate, blood pressure) were compared, and blood concentrations of ethanol, acetaldehyde, pyruvate, lactate, hydrocarbonates as well as blood pH, pO2 and pCO2 were determined in fasting state and during 6 hours after alcohol ingestion. In all patients the family history of diabetes and the presence and degree of vascular complications were registered. Evident flushing phenomenon was observed in 6 patients treated with chlorpropamide, in 3 treated with tolbutamide, in 2 treated with glibenclamide, in one receiving glibornuride and in none treated with glipizide. All drugs caused a greater rise of blood ethanol and acetaldehyde levels in relation to the control tests, but the difference reached statistical significance only in the group receiving chlorpropamide. Moreover, patients (pooled) with positive thermographic response had also significantly higher blood levels of ethanol and acetaldehyde during the second test. The ratio of acetaldehyde to ethanol concentration in blood (mumol:mmol) was not significantly changed in any group indicating parallel impairment of both steps of ethanol metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

[Alcohol tolerance in patients with non-insulin-dependent diabetes (type 2) treated orally with drugs--derivatives of sulphonylurea]. / Tolerancja alkoholu przez chorych na cukrzyce nie-insulinozalezna (typu 2) leczonych lekami doustnymi--pochodnymi sulfonylomocznika.

The oral ethanol loading test (0.5 g per kg b.m. given as 40% solution) was carried out in 5 groups, each of 10 patients with non-insulin-dependent (type 2) diabetes before and after 10 days of treatment with one of the following sulphonylurea derivatives: tolbutamide 0.5 t.i.d., chlorpropamide 0.5 once daily morning, glibornuride 0.025 t.i.d, glibenclamide 0.005 t.i.d. and glipizide 0.005 t.i.d. The response to alcohol (facial flush, heart rate, blood pressure) were compared, and blood concentration of ethanol, acetaldehyde, pyruvate, lactate, carbonates as well as blood pH, pO2 and pCO2 were determined in fasting state and during 6 hours after alcohol ingestion. In all patients the family history of diabetes and the presence and degree of vascular complications were registered. Evident flushing phenomenon was observed in 6 patients treated with chlorpropamide, in 3 treated with tolbutamide, in 2 treated with glibenclamide, in one receiving glibornuride and in none treated with glipizide. All drugs caused a greater rise of blood ethanol and acetaldehyde levels in relation to the control tests, but the difference reached statistical significance only in the group receiving chlorpropamide. Moreover, patients (pooled) with positive thermographic response had also significantly higher blood levels of ethanol and acetaldehyde during the second test. The ratio of acetaldehyde to ethanol concentration in blood (mumol:mmol) was not significantly changed in any group indicating parallel impairment of both steps of ethanol metabolism. All studied drugs intensified to a similar degree the alcohol-induced hypoglycaemia, but had no significant effect on the decrease of blood pyruvate level neither on the increase of blood lactate level. They didn't change the post-alcohol decrease of blood bicarbonate and pH, and didn't modify the behaviour of partial gas pressure. There was also no difference between pooled groups of patients with positive and negative thermographic reaction with respect to family history of diabetes and frequency and intensity of vascular complications. It is concluded that in patients with non-insulin-dependent (type 2) diabetes the second generation sulphonylurea derivatives are associated with lower risk of alcohol intolerance in case of its incidental ingestion in small amounts. The hypothesis of association of positive thermographic reaction to alcohol during treatment with sulphonylurea derivatives with more frequent occurrence of diabetes in family members and lower tendency to vascular complications was not confirmed.

[Specificity of cytochrome P-450 forms in the rat liver after inhalation of multicomponent hydrocarbon mixture]. / Specyficznosc form cytochromu P-450 w watrobie szczura inhalowanego wieloskladnikowa mieszanina weglowodorów.

Rats were inhaled with C6-C9 petroleum fraction 12 hrs daily for 9 days. The hydrocarbons and their metabolites gas chromatographic profiles from liver, kidney, brain and blood were investigated by means of head space technique. The observed characteristic profile composed of some hydrocarbons and secondary alcohols does not undergo qualitative changes and internal quantitative proportions remain constant in spite of cytochrome P-450 induction. Only total amount of hydrocarbons and their metabolites was varied. The results suggest that C6-C9 petroleum fraction inhalation does not induce new forms of cytochrome P-450 with different catalytic properties, but at the same time substrate binding site is modified to facilitate biotransformation of hydrocarbons and their metabolites.

[Spectral interactions of cytochrome P-450 with n-heptane and methanol]. / Interakcje spektralne cytochromu P-450 z n-heptanem i metanolem.

Methanol interacts with cytochrome P-450 to produce the reversed type I spectral change. In the presence of type I substrate n-heptane, the methanol induced spectrum disappears without detectable effects of interaction suggesting that methanol is a very weak ligand for heme iron of cytochrome P-450. Methanol strongly lowers the apparent spectral dissociation constant (Ks app) of n-heptane binding with rat liver cytochrome P-450 both in control and C6-C9 petroleum fraction inhaled group. In control group, titration of cytochrome P-450 with methanolic solutions of n-heptane does not change the maximal spectral interaction (Amax) observed with pure n-heptane. However in the inhaled group during titration of induced cytochrome P-450 with methanolic solutions of n-heptane an additional type I spectral change is observed. Thus addition of "equivalent" amounts of methanol into the reference cuvette during titration with methanolic solutions overestimates the true magnitude of type I spectral change of cytochrome P-450 with n-heptane.

Effect of two-week ethanol administration on lipoprotein lipase activity and blood serum lipids in the rat.

Influence of ethanol administration on adipose tissue lipoprotein lipase activity, serum lipids in the rat. Intoxication caused a decrease of lipoprotein lipase activity. In some animals a rise of serum high density lipoprotein cholesterol was observed which correlated positively with the content of cytochrome P-450 in the liver.

Properties of reconstituted rabbit pulmonary mixed-function oxidase system with cytochrome P-450.

Reconstituted rabbit pulmonary mixed-function oxidase (MFO) system is composed of four components: NADPH cytochrome P-450 reductase, cytochrome P-450, phosphatidylcholine and cholate. Evidence has been presented that phosphatidylcholine and cholate form micelles that take an active part in the reconstitution. Order of addition of MFO system components in the reconstitution has been intensively studied. Several titration curves well describe reconstituted system. Experimental data suggest formation of dissociable complex of reductase, cytochrome P-450 and micelles A model for reconstituted rabbit pulmonary MFO system is discussed.

Effect of sodium cholate on the NADPH cytochrome P-450 reductase activity in the reconstituted rabbit pulmonary mixed-function oxidase system.

Solubilization, separation and purification procedures for rabbit pulmonary mixed-function oxidase (MFO) system have been shown to influence the NADPH cytochrome P-450 reductase component activity in the reconstituted system. The reductase activity as judged by cytochrome c reduction does not correlate with the reductase ability to interact with other MFO system components. Sodium cholate used in several solubilization and purification procedures may alter the reconstituted drug metabolizing activity.

Effect of neutral lipids on the activity of rabbit pulmonary mixed-function oxidase system with cytochrome P-450.

With increasing amount of cholesterol or neutral lipids, an increase with subsequent inhibition of the reconstituted rabbit pulmonary mixed-function oxidase (MFO) system activity is observed. Lecithin-cholate micelles formed in the reconstituted system may reverse the inhibitory effect of neutral lipids excess. Neutral lipids do not constitute essential component of the reconstituted MFO system however small quantities of neutral lipids may modify the structure of MFO system components to yield the highest 7-EC O-deethylation activities.

Towards standardization of the reconstituted mixed function oxidase systems with cytochrome P-450.

Reconstituted rabbit pulmonary mixed function oxidase (MFO) system with cytochrome P-450 is composed of NADPH cytochrome P-450 reductase, cytochrome P-450, phospholipid extract and cholate. Factors essential for the reconstitution of the active system include the component concentrations and ratios, preincubation and the ionic strength of the buffer. The rabbit pulmonary MFO system can be separated, purified and reconstituted with good reproducibility. However there are many factors influencing reconstituted activity mainly associated with the reconstitution and reductase purification procedure.

The rabbit pulmonary monooxygenase system: characteristics and activities of two forms of pulmonary cytochrome P-450.

Two forms of rabbit pulmonary cytochrome P-450 have been characterized spectrally and their activities in reconstituted monooxygenase systems investigated. The presence of both microsomal phospholipids and sodium cholate was required to obtain optimum activity. Only one of the cytochromes (I) was active in the N-demethylation of benzphetamine and the O-deethylation of 7-ethoxycoumarin. However, cytochrome II was 20% more active than cytochrome I in the metabolism of benzo[a]pyrene. The profile of the metabolites formed from benzo[a]pyrene indicated that metabolism at the 9 and 10 positions was insignificant in the case of cytochrome I but represented about 40% of the metabolites produced by cytochrome II. The two forms of the cytochrome are present in pulmonary microsomes in approximately equal amounts.

Effect of ethanol on subcellular metal distribution in rat liver.

The effect of ethanol on the subcellular distribution of Mn, Cu, Zn, Mg and Cr in rat liver has been investigated. Significant changes in Mg, Zn and Mn distribution have been observed. No change in the microsomal Mn, Cu, Zn, Mg and Cr content has been found.