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C S Lieber

Publications and source records attributed to C S Lieber.

At least 19 recordsLinked to original sources
PubMed2005

Pathogenesis and treatment of alcoholic liver disease: progress over the last 50 years.

Fifty years ago the dogma prevailed that alcohol was not toxic to the liver and that alcoholic liver disease was exclusively a consequence of nutritional deficiencies. We showed, however, that liver pathology developed even in the absence of malnutrition. This toxicity of alcohol was linked to its metabolism via alcohol dehydrogenase which converts nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide-reduced form (NADH) which contributes to hyperuricemia, hypoglycemia and hepatic steatosis by inhibiting lipid oxidation and promoting lipogenesis. We also discovered a new pathway of ethanol metabolism, the microsomal ethanol oxidizing system (MEOS). The activity of its main enzyme, cytochrome P4502E1 (CYP2E1), and its gene are increased by chronic consumption, resulting in metabolic tolerance to ethanol. CYP2E1 also detoxifies many drugs but occasionally toxic and even carcinogenic metabolites are produced. This activity is also associated with the generation of free radicals with resulting lipid peroxidation and membrane damage as well as depletion of mitochondrial reduced glutathione (GSH) and its ultimate precursor, namely methionine activated to S-adenosylmethionine (SAMe). Its repletion restores liver functions. Administration of polyenylphosphatidylcholine (PPC), a mixture of unsaturated phosphatidylcholines (PC) extracted from soybeans, restores the structure of the membranes and the function of the corresponding enzymes. Ethanol impairs the conversion of beta-carotene to vitamin A and depletes hepatic vitamin A and, when it is given together with vitamin A or beta-carotene, hepatotoxicity is potentiated. Our present therapeutic approach is to reduce excess alcohol consumption by the Brief Intervention technique found to be very successful. We correct hepatic SAMe depletion and supplementation with PPC has some favorable effects on parameters of liver damage which continue to be evaluated. Similarly dilinoleoylphosphatidylcholine (DLPC), PPC's main component, also partially opposes the increase in CYP2E1 by ethanol. Hence, therapy with SAMe +DLPC is now being considered.

Animals↗
PubMed2001

Dilinoleoylphosphatidylcholine decreases ethanol-induced cytochrome P4502E1.

Cytochrome P4502E1 (CYP2E1) induction by ethanol contributes to alcoholic liver disease and we found that a mixture of polyunsaturated phosphatidylcholines (PPC), which protects against alcohol-induced liver injury, also decreases CYP2E1. Since dilinoleoylphosphatidylcholine (DLPC) is the major component of PPC, we assessed here whether it is responsible for the protection of PPC by feeding rats for 8 weeks our liquid diet containing ethanol (36% of energy) or isocaloric carbohydrates, with either DLPC (1.5 g/1000 cal), PPC (3 g/1000 cal), or linoleate. CYP2E1 was assessed by Western blots and by two of its enzyme activities: the microsomal ethanol-oxidizing system (MEOS) and p-nitrophenolhydroxylase (PNP). With ethanol, CYP2E1 increased 10-fold, with corresponding rises in PNP and MEOS activities. Compared to linoleate, DLPC significantly decreased cytochrome b(5), total cytochromes P450, CYP2E1 content and its corresponding activities. DLPC decreases ethanol-induced CYP2E1 and should be considered for the prevention of alcoholic liver disease.

Animals↗
PubMed2001

Alcoholic liver injury: pathogenesis and therapy in 2001.

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of prevention and promising prospects for even more effective treatments. It continues to be important to replenish nutritional deficiencies when present but it is crucial to recognize that, because of the alcohol-induced disease process, some of the nutritional requirements change. For instance, methionine, one of the essential amino acids for humans, must be activated to SAMe but, in severe liver disease, the activity of the corresponding enzyme is depressed. Therefore, the resulting deficiencies and associated pathology can be attenuated by the administration of SAMe, but not by methionine. Similarly, phosphatidylethanolamine methyltransferase (PEMT) activity, which is important for hepatic phosphatidylcholine (PC) synthesis, is also depressed in alcoholic liver disease, therefore calling for administration of the products of the reaction. It might also be beneficial to add other compounds to such therapeutic regiment. Since free radical generation by the ethanol-induced CYP2E1 plays a key role in the oxidative stress, inhibitors of this enzyme have great promise. Several have been investigated experimentally and PPC is particularly interesting because of its innocuity. In view of the striking negative interaction between alcoholic liver injury and hepatitis C, an antiviral agent is eagerly awaited that, unlike Interferon, is not contraindicated in the alcoholic. Anti-inflammatory agents are also required. In addition to down-regulators of cytokines and end toxic are being considered. Finally, since excess drinking is the crux of the issue, anticraving agents should be incorporated in any contemplated therapeutic cocktail, in view of the recent promising results obtained with some of these agents such as naltrexone and acamprosate.

Ethanol↗
PubMed2001

Liver diseases by alcohol and hepatitis C: early detection and new insights in pathogenesis lead to improved treatment.

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of treatment. Therapy must include correction of nutritional deficiencies, while taking into account changes of nutritional requirements. Methionine is normally activated to S-adenosylmethionine (SAMe). However, in liver disease, the corresponding enzyme is depressed. The resulting deficiencies can be attenuated by the administration of SAMe but not by methionine. Similarly, phosphatidylethanolamine methyltransferase activity is depressed, but the lacking phosphatidylcholine (PC) can be administrated as polyenylphosphatidylcholine (PPC). Chronic ethanol consumption increases CYP2E1, resulting in increased generation of toxic acetaldehyde and free radicals, tolerance to ethanol and other drugs, and multiple ethanol-drug interactions. Experimentally, PPC opposes CYP2E1 induction and fibrosis. Alcoholism and hepatitis C infection commonly co-exist, with acceleration of fibrosis, cirrhosis, and hepatocellular carcinoma. PPC is being tested clinically as a corresponding antifibrotic agent. Available antiviral agents are contraindicated in the alcoholic. Anti-inflammatory agents, such as steroids, may be selectively useful. Finally, anticraving agents, such as naltrexone or acamprosate, should be part of therapy.

Ethanol↗
PubMed2001

Alcohol and retinoids.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Hirokazu Yokoyama and David Crabb. The presentations were (1) Roles of vitamin A, retinoic acid, and retinoid receptors in the expression of liver ALDH2, by J. Pinaire, R. Hasanadka, M. Fang, and David W. Crabb; (2) Alcohol, vitamin A, and beta-carotene: Adverse interactions, by M. A. Leo and Charles S. Lieber; (3) Retinoic acid, hepatic stellate cells, and Kupffer cells, by Hidekazu Tsukamoto, K. Motomura, T. Miyahara, and M. Ohata; (4) Retinoid storage and metabolism in liver, by William Bosron, S. Sanghani, and N. Kedishvili; (5) Characterization of oxidation pathway from retinol to retinoic acid in esophageal mucosa, by Haruko Shiraishi, Hirokazu Yokoyama, Michiko Miyagi, and Hiromasa Ishii; and (6) Ethanol in an inhibitor of the cytosolic oxidation of retinol in the liver and the large intestine of rats as well as in the human colon mucosa, by Ina Bergheim, Ina Menzl, Alexandr Parlesak, and Christiane Bode.

Aldehyde Dehydrogenase↗
PubMed2001

Models of alcoholic liver disease in rodents: a critical evaluation.

This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were J. Christian Bode and Hiroshi Fukui. The presentations were (1) Essentials and the course of the pathological spectrum of alcoholic liver disease in humans, by P. de la M. Hall; (2) Lieber-DeCarli liquid diet for alcohol-induced liver injury in rats, by C. S. Lieber and L. M. DeCarli; (3) Tsukamoto-French model of alcoholic liver injury, by S. W. French; (4) Animal models to study endotoxin-ethanol interactions, by K. O. Lindros and H. Järveläinen; and (5) Jejunoileal bypass operation in rats-A model for alcohol-induced liver injury? by Christiane Bode, Alexandr Parlesak, and J. Christian Bode.

Animals↗
PubMed2001

Azide inhibits human cytochrome P -4502E1, 1A2, and 3A4.

BACKGROUND: Recently, we showed that, in addition to cytochrome P-4502E1 (CYP2E1), CYP1A2 and CYP3A4 also contribute to the microsomal ethanol oxidizing system (MEOS). When MEOS activity is measured, sodium azide commonly is used to block the contaminating catalase. However, although CYP2E1 is considered insensitive to azide, its effect on the other P-450s is unknown. Therefore, the aim of the present study was to determine the effect of azide on human recombinant and hepatic CYP2E1, CYP1A2, and CYP3A4. METHODS AND RESULTS: Concentrations of sodium azide as low as 0.1 mM markedly inhibited the specific ethanol oxidation (mean +/- SEM) by recombinant CYP1A2 and CYP3A4 expressed in HepG2 cells (to 16 +/- 1% and 22 +/- 2% of control without azide, respectively; p < 0.01). By contrast, the specific activity of CYP2E1 was only slightly (and not significantly) inhibited at this azide concentration (to 79 +/- 12% of control). Similarly, in human liver microsomes (n = 6), 0.1 mM azide strongly inhibited CYP1A2-dependent (to 25 +/- 2%) and CYP3A4-dependent (to 15 +/- 2%) ethanol oxidation, whereas CYP2E1 was inhibited only at 10 mM azide (to 60 +/- 10%). Azide also strongly affected the apparent kinetic values of all three isoenzymes. Furthermore, azide inhibited the specific monooxygenase activities, both by recombinant and microsomal P-450s. CYP2E1-specific p-nitrophenol hydroxylation was the most sensitive to azide, whereas CYP1A2-dependent 7-methoxyresorufin O-dealkylation was only slightly inhibited. Judging from its effect on p-nitrophenol hydroxylation by human liver microsomes, the inhibition of azide was competitive (Ki 0.09 mM). CONCLUSIONS: Sodium azide at a concentration as low as 0.1 mM inhibited ethanol oxidation by CYP1A2 and CYP3A4. With CYP2E1, although oxidation of 50 mM ethanol was not inhibited by 0.1 mM azide, higher azide concentrations were inhibitory and 0.1 mM azide seemed to affect the kinetics of ethanol oxidation by CYP2E1. Therefore, azide should be avoided when measuring the MEOS activity because it may lead to underestimation, especially of CYP1A2- and CYP3A4-dependent ethanol oxidation.

Binding, Competitive↗
PubMed2001

Gender differences in pharmacokinetics of alcohol.

BACKGROUND: The enhanced vulnerability of women to develop alcohol-related diseases may be due to their higher blood alcohol levels after drinking, but the mechanism for this effect is debated. METHODS: Sixty-five healthy volunteers of both genders drank 0.3 g of ethanol/kg of body weight (as 5%, 10%, or 40% solutions) postprandially. Blood alcohol concentrations were monitored by breath analysis and compared with those after intravenous infusion of the same dose. First-pass metabolism was quantified (using Michaelis-Menten kinetics) as the route-dependent difference in the amount of ethanol reaching the systemic blood. Gastric emptying was assessed by nuclear scanning after intake of 300 microCurie of technetium-labeled diethylene triamine pentacetic acid in 10% ethanol. The activities of alcohol dehydrogenase isozymes were assessed in 58 gastric biopsies, using preferred substrates for gamma-ADH (acetaldehyde) and for final sigma-ADH (m-nitrobenzaldehyde) and a specific reaction of chi-ADH (glutathione-dependent formaldehyde dehydrogenase). RESULTS: Women had less first-pass metabolism than men when given 10% or 40%, but not 5%, alcohol. This was associated with lower gastric chi-ADH activity; its low affinity for ethanol could explain the greater gender difference in first-pass metabolism with high rather than with low concentrations of imbibed alcohol. Alcohol gastric emptying was 42% slower and hepatic oxidation was 10% higher in women. A 7.3% smaller volume of alcohol distribution contributed to the higher ethanol levels in women, but it did not account for the route-dependent effects. CONCLUSIONS: The gender difference in alcohol levels is due mainly to a smaller gastric metabolism in females (because of a significantly lesser activity of chi-ADH), rather than to differences in gastric emptying or in hepatic oxidation of ethanol. The concentration-dependency of these effects may explain earlier discrepancies. The combined pharmacokinetic differences may increase the vulnerability of women to the effects of ethanol.

Adult↗
PubMed2001

Effect of beta-carotene on hepatic cytochrome P-450 in ethanol-fed rats.

BACKGROUND: Hepatotoxicity of ethanol is increased by beta-carotene in both rodents and nonhuman primates. Furthermore, in smokers who are also drinkers, beta-carotene increases the incidence of pulmonary cancer. The hepatotoxicity was associated with proliferation of the membranes of the smooth endoplasmic reticulum, suggesting the involvement of cytochromes P-450. Therefore, the aim of the present study was to assess the effect of beta-carotene and ethanol treatment on rodent hepatic cytochromes P-450. METHODS AND RESULTS: Weanling male Sprague-Dawley rats were pair-fed beta-carotene (56.5 mg/l of diet) for 8 weeks, with and without ethanol (Lieber-DeCarli, 1994 liquid diet). As expected, ethanol increased CYP2E1 (measured by Western blots) from 67 +/- 8 to 317 +/- 27 densitometric units (p < 0.001). Furthermore, beta-carotene potentiated the ethanol induction to 442 +/- 38 densitometric units (p < 0.01) with a significant interaction (p = 0.012). The rise was confirmed by a corresponding increase in the hydroxylation of p-nitrophenol, a specific substrate for CYP2E1, and by the inhibition with diethyl dithiocarbamate (50 microM). Beta-carotene alone also significantly induced CYP4A1 protein (328 +/- 49 vs. 158 +/- 17 densitometric units, p < 0.05). The corresponding CYP4A1 mRNA (measured by Northern blots) was also increased (p < 0.05) and there was a significant interaction of the two treatments (p = 0.015). The combination of ethanol and beta-carotene had no significant effect on either total cytochrome P-450 or CYP1A1/2, CYP2B, CYP3A, and CYP4A2/3 contents. CONCLUSIONS: Beta-carotene potentiates the CYP2E1 induction by ethanol in rat liver and also increases CYP4A1, which may, at least in part, explain the associated hepatotoxicity.

Animals↗
PubMed2001

Alcohol and hepatitis C.

Infection with the hepatitis C virus (HCV) has become a leading cause of scarring of the liver (i.e., fibrosis) and cirrhosis in the United States. HCV-related cirrhosis (with its associated complications, such as liver cancer) is a major cause of death, although it develops slowly and occurs only in approximately one-third of HCV-infected patients. Alcohol can exacerbate HCV infection and the associated liver damage by causing oxidative stress and promoting fibrosis, thereby accelerating disease progression to cirrhosis. Furthermore, alcohol may exacerbate the side-effects associated with current antiviral treatment of HCV infection and impair the body's immune defense against the virus. Of the HCV-infected people who do not consume alcohol, only a minority progresses to severe liver disease and requires antiviral treatment. Because alcohol potentiates the fibrosis- and cancer-inducing actions of HCV, alcoholics are particularly vulnerable to HCV infection and most in need of treatment.

Alcoholism↗
PubMed2000

Blood group antigen expression in the rat colon I. age-dependent and region-related changes.

The blood group antigens H, A, B, and Le(b) are oncofetal antigens of the human distal colon. Although these antigens are present in the digestive mucosa of the rat, little is known about their ontogenic expression in the developing rat colon. The present study was undertaken to assess age-dependent and region-related changes of blood group antigens during colonic development and maturation with the aim of determining their fetal phenotype. Antigen expression was assessed by immunohistochemistry using H-, A-, B-, Le(a)-, and Le(b)-specific monoclonal antibodies and formalin-fixed, paraffin-embedded colon sections from fetal, suckling, weanling, and adult rats. Staining of antigen was analyzed with respect to its locations in colonic goblet cells, brush borders, and columnar cells. H, B, and Le(b) antigens were expressed by goblet cells of the distal colon, beginning at 20 days of gestation, but expression was lost from the colon during the first postnatal week, thus exhibiting a fetal phenotype. H and Le(b), but not B, were also expressed by goblet cells of the fetal proximal colon; however, unlike that of the distal colon, their expression increased progressively during postnatal development until adulthood. Fetal phenotypic expression was observed in the brush border of the proximal and distal colon for H antigen, whereas it was observed in that of the distal colon for B antigen. No fetal phenotypic expression of H, B, and Le(b) by columnar cells of the colon was observed. Antigen A was expressed by goblet cells, brush border, and columnar cells of the entire colon at all ages, in concert with the development and maturation of the colon. Therefore, its expression in the rat colon was not fetal in nature. Le(a) was not detected in the colon at any age, except for some sporadic staining in the Golgi zone of columnar cells of the postnatal proximal colon. In conclusion, these data indicate significant age- and region-related changes of blood group antigen expression in the rat colon. Because the fetal phenotypic expression of H, B, and Le(b) by goblet cells of the distal colon mimics that in the human distal colon, the adult rat colon is a potentially useful model for assessing the effects of cocarcinogenic dietary factors, including ethanol, that may induce reexpression of these so-called oncofetal tumor-associated antigens of the colon.

ABO Blood-Group System↗
PubMed2000

Blood group antigen expression in the rat colon II. Modulation by dietary ethanol consumption.

In the accompanying article, we established that in the rat distal colon expression of H, B, and Le(b) blood group antigens by goblet cells is phenotypically fetal in nature. Because of the cocarcinogenic property of ethanol, the present study examined the effects of dietary ethanol consumption, fasting, and withdrawal on the expression of these antigens in the adult rat colon. To that effect, male adult Sprague-Dawley rats were pair-fed ethanol-containing or control Lieber-DeCarli liquid diets for 3 weeks. The effects of ethanol withdrawal were studied in rats fed the ethanol-containing diet for 3 weeks followed by the control diet for 1, 3, and 6 days. In rats fed the control diet, no antigen expression in the distal colon was observed, as expected. Ethanol feeding for 3 weeks resulted in a striking reappearance of H, B, and Le(b) antigens in goblet cells of the distal colon. In colonic crypts, a lower-to-upper crypt gradient of increasing numbers of positive goblet cells was present, suggesting that the induction of antigen expression paralleled the differentiation of goblet cells. After an overnight fast, the number of positive cells was significantly decreased. Withdrawal of ethanol for 1 day further decreased the number of positive goblet cells. The decrease was reflected by a downward shift in the number of positive cells per crypt column, which was more striking in the lower and mid-crypt segments than in the upper segment, suggesting that antigen expression was more labile in immature differentiating goblet cells than in mature ones. No antigen staining of goblet cells was detected after 3 and 6 days of ethanol withdrawal. Hence, expression of H, B, and Le(b) antigens by goblet cells of the distal colon can be modulated by ethanol consumption. Expression in the distal colon of A and Le(a) antigens, which did not exhibit a fetal phenotype, was not affected by ethanol feeding. In conclusion, because of the oncofetal phenotype of H, B, and Le(b) antigens, their reappearance in the distal colon may serve as a cytochemical marker for early recognition of epithelial changes of the colon in ethanol-related cocarcinogenesis before more overt manifestations of neoplasia.

Alcohol Drinking↗
PubMed2000

Dilinoleoylphosphatidylcholine protects human low density lipoproteins against oxidation.

LDL oxidation may promote atherosclerosis. We found that polyenyphosphatidylcholine (PPC), a mixture of polyunsaturated phospholipids extracted from soybeans, has antioxidant effects in in vivo models of oxidative stress. To assess whether components of PPC affect the in vitro oxidizability of LDL, plasma from 15 healthy volunteers was incubated with 10 microM of either dilinoleoyl-, palmitoyl-linoleoyl-, linoleoyl-palmitoyl- or distearoyl-phosphatidylcholine as well as 10 microM and 1 mM alpha-tocopherol. LDL oxidation was initiated with 5 microM Cu(2+) sulfate and monitored by conjugated diene production, or with 2, 2'-azobis (2-amidinopropane) dihydrochloride, a free radical generator, and monitored by O(2) consumption. After addition of Cu(2+), the lag phase (indicative of resistance of LDL to oxidation) was longer (140% of controls; P<0.001) for LDL incubated with dilinoleoyl-, but not with the other phosphatidylcholine species. This effect was similar to that of 1 mM alpha-tocopherol (135%). After addition of 2,2'-azobis (2-amidinopropane) dihydrochloride, the inhibition time (also reflecting the antioxidant content of LDL) was prolonged (P<0.001) for alpha-tocopherol (206%) and dilinoleoyl-(188%), but not for distearoyl-phosphatidyl-choline. Thus, dilinoleoyl-phosphatidylcholine (the main component of PPC) protects against LDL oxidation, a possible mechanism for its reported anti-atherosclerosis effects.

Adult↗
PubMed2000

Alcoholic liver disease: new insights in pathogenesis lead to new treatments.

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of prevention and therapy, with promising prospects for even more effective treatments. The most successful approaches that one can expect to evolve are those that deal with the fundamental cellular disturbances resulting from excessive alcohol consumption. Two pathologic concepts are emerging as particularly useful therapeutically. Whereas it continues to be important to replenish nutritional deficiencies, when present, it is crucial to recognize that because of the alcohol-induced disease process, some of the nutritional requirements change. This is exemplified by methionine, which normally is one of the essential amino acids for humans, but needs to be activated to S-adenosylmethionine (SAMe), a process impaired by the disease. Thus, SAMe rather than methionine is the compound that must be supplemented in the presence of significant liver disease. Indeed, SAMe was found to attenuate mitochondrial lesions in baboons, replenish glutathione, and significantly reduce mortality in patients with Child A or B cirrhosis. Similarly, polyenylphosphatidylcholine (PPC) corrects the ethanol-induced hepatic phospholipid depletion as well as the decreased phosphatidylethanolamine methyltransferase activity and opposes oxidative stress. It also deactivates hepatic stellate cells, whereas its dilinoleoyl species (DLPC) increases collagenase activity, resulting in prevention of ethanol-induced septal fibrosis and cirrhosis in the baboon. Clinical trials with PPC are ongoing in patients with alcoholic liver disease. Furthermore, enzymes useful for detoxification, such as CYP2E1, when excessively induced, become harmful and should be downregulated. PPC is one of the substances with anti-CYP2E1 properties that is now emerging. Another important aspect is the association of alcoholic liver disease with hepatitis C: a quarter of all patients with alcoholic liver disease also have markers of HCV infection, with an even higher incidence in some urban areas but, at present, no specific therapy is available since interferon is contraindicated in that population. However, in addition to antiviral medications, agents that oppose oxidative stress and fibrosis should also be tested for hepatitis C treatment since these two processes contribute much to the pathology and mortality associated with the virus. In addition to antioxidants (such as PPC, silymarin, alpha-tocopherol and selenium), anti-inflammatory medications (corticosteroids, colchicine, anticytokines) are also being tested as antifibrotics. Transplantation is now accepted treatment in alcoholics who have brought their alcoholism under control and who benefit from adequate social support but organ availability is still the major limiting factor and should be expanded more aggressively. Finally, abstinence from excessive drinking is always indicated; it is difficult to achieve but agents that oppose alcohol craving are becoming available and they should be used more extensively.

Animals↗
PubMed2000

Hepatic, metabolic, and nutritional disorders of alcoholism: from pathogenesis to therapy.

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in an improvement in treatment. Nutritional deficiencies should be corrected when present but, because of the alcohol-induced disease process, some of the nutritional requirements change. For instance, methionine, one of the essential amino acids for humans, must be activated to S-adenosylmethionine (SAMe), but, in severe liver disease, the activity of the corresponding enzyme is depressed. Therefore, the resulting deficiencies and associated pathology can be attenuated by the administration of SAMe, but not by methionine. Similarly, phosphatidylethanolamine methyltransferase (PEMT) activity, which is important for hepatic phosphatidylcholine (PC) synthesis, is also depressed in alcoholic liver disease, therefore calling for the administration of the products of the reaction. Inasmuch as free radical generation by the ethanol-induced CYP2E1 plays a key role in the oxidative stress, inhibitors of this enzyme have great promise and PPC, which is presently being evaluated clinically, is particularly interesting because of its innocuity. In view of the striking negative interaction between alcoholic liver injury and hepatitis C, an antiviral agent is eagerly awaited that, unlike Interferon, is not contraindicated in the alcoholic. Antiinflamatory agents may also be useful. In addition to steroids, down-regulators of cytokines and endotoxin are being considered. Finally, anticraving agents such as naltrexone or acamprosate should be incorporated into any contemplated therapeutic cocktail.

Alcoholism↗
PubMed2000

Alcohol levels are increased in social drinkers receiving ranitidine.

OBJECTIVE: Ranitidine increases blood alcohol concentrations by decreasing the first pass metabolism of ethanol. The effect of ranitidine on alcohol levels has been found to be variable when using large doses of alcohol or conditions in which its first pass metabolism is known to be minimal. Despite a consensus that the drug increases alcohol levels after small doses of ethanol, this effect has been considered inconsequential, because of the low alcohol levels. However, social drinking comprises repetitive consumption of small doses of alcohol and the ranitidine effect could thereby be potentiated. METHODS: To study this factor, alcohol levels were determined by breath analysis in nine men (social drinkers), after four drinks of 0.15 g/kg ethanol given postprandially every 45 min, before and after ranitidine (150 mg b.i.d. for 7 days). RESULTS: Their blood alcohol increased with repeated doses, reaching peak values of 24+/-3 mg/dl before ranitidine and 33+/-2 after ranitidine (p = 0.04). In seven of the nine subjects blood alcohol exceeded 25 mg/dl, a level at which impairment of judgment and of finely tuned skills occurs and which exceeds legal limits of driving in some European countries. Moreover, the high levels persisted for a longer time with than without the drug. These effects were associated with a 62% decrease in first pass metabolism. CONCLUSION: Under conditions mimicking social drinking, ranitidine increases blood alcohol to levels known to impair psychomotor skills needed for driving.

Adult↗
PubMed2000

ALCOHOL: its metabolism and interaction with nutrients.

In the past, alcoholic liver disease was attributed exclusively to dietary deficiencies, but experimental and judicious clinical studies have now established alcohol's hepatotoxicity. Despite an adequate diet, it can contribute to the entire spectrum of liver diseases, mainly by generating oxidative stress through its microsomal metabolism via cytochrome P4502E1 (CYP2E1). It also interferes with nutrient activation, resulting in changes in nutritional requirements. This is exemplified by methionine, one of the essential amino acids for humans, which needs to be activated to S-adenosylmethionine (SAMe), a process impaired by liver disease. Thus, SAMe rather than methionine is the compound that must be supplemented in the presence of significant liver disease. In baboons, SAMe attenuated mitochondrial lesions and replenished glutathione; it also significantly reduced mortality in patients with Child A or B cirrhosis. Similarly, decreased phosphatidylethanolamine methyltransferase activity is associated with alcoholic liver disease, resulting in phosphatidylcholine depletion and serious consequences for the integrity of membranes. This can be offset by polyenylphosphatidylcholine (PPC), a mixture of polyunsaturated phosphatidylcholines comprising dilinoleoylphosphatidylcholine (DLPC), which has high bioavailability. PPC (and DLPC) opposes major toxic effects of alcohol, with down-regulation of CYP2E1 and reduction of oxidative stress, deactivation of hepatic stellate cells, and increased collagenase activity, which in baboons, results in prevention of ethanol-induced septal fibrosis and cirrhosis. Corresponding clinical trials are ongoing.

Alcohol Dehydrogenase↗