Beta carotene, vitamin E, and lung cancer.
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Alcoholism↗
Biomedical subjects
M A Leo
Publications and source records attributed to M A Leo.
Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon.
BACKGROUND/AIMS: Polyunsaturated soybean lecithin (55%-60% phosphatidylcholine [PC]) protects against fibrosis in alcohol-fed baboons. The present study was undertaken to determine whether PC is the active agent. METHODS: Virtually pure PC (equivalent to that contained in the lecithin) was administered for up to 6.5 years with or without alcohol, and the results were compared with those of unsupplemented groups. RESULTS: Control livers remained normal, whereas 10 of 12 baboons fed alcohol without PC developed septal fibrosis or cirrhosis with transformation of 81% +/- 3% of the hepatic lipocytes to collagen-producing transitional cells. By contrast, none of the eight animals fed alcohol with PC developed septal fibrosis or cirrhosis, and only 48% +/- 9% of their lipocytes were transformed, indicating that PC was indeed the protective compound. Ethanol feeding also resulted in decreased liver phospholipids and PC, and both were corrected by the supplementation. Furthermore, PC stimulated collagenase activity in cultured lipocytes. This PC consisted of several species, mainly dilinoleoylphosphatidylcholine (40%-52%) and palmitoyl-linoleoylphosphatidylcholine (23%-24%). Only dilinoleoylphosphatidylcholine duplicated the effect of the PC on collagenase. Other species of PC, phosphatidylethanolamine, free fatty acids, or choline were without effect. CONCLUSIONS: PC prevents alcohol-induced fibrosis and cirrhosis in nonhuman primates, and dilinoleoylphosphatidylcholine appears to be the active species, possibly by promoting collagen breakdown.
Animals↗
Interactions between alcohol and beta-carotene in patients with alcoholic liver disease.
We found lower plasma beta-carotene concentrations in alcoholics than in control subjects, but heavy drinkers (> or = 200 g/d) had about twice the beta-carotene of those drinking less (P < 0.01), with a significant correlation between plasma beta-carotene and alcohol intake (r = 0.6, P < 0.001). When beta-carotene beadlets (30-60 mg/d) were administered to hospitalized alcoholics given controlled diets, those with cirrhosis had a much lower plasma beta-carotene response than those without; the latter in turn responded with lower beta-carotene concentrations than did control subjects. Plasma retinol, alpha-tocopherol, and other carotenoids, such as lycopene, did not differ significantly. We concluded that plasma beta-carotene is relatively increased by heavy alcohol consumption, whereas in patients with liver damage, especially cirrhosis, it is lowered. In these patients, beta-carotene supplementation may be justified, but this should be coupled with control of drinking because of possible hepatotoxic alcohol-beta-carotene interactions.
Adult↗
Hepatic phosphatidylethanolamine methyltransferase activity is decreased by ethanol and increased by phosphatidylcholine.
UNLABELLED: Phosphatidylethanolamine N-methyltransferase participates in the synthesis of membrane phosphatidylcholine. Its activity was reported to be decreased in patients with alcoholic cirrhosis, but it is not known whether this is a consequence of the cirrhosis or precedes it. This question was studied in a baboon model of alcohol-induced fibrosis. Phosphatidylethanolamine N-methyltransferase activity was measured in sequential percutaneous needle liver biopsies by the conversion of phosphatidylethanolamine to phosphatidylcholine, using radioactive S-adenosylmethionine as a methyl donor. Chronic alcohol consumption (1-6 years) significantly decreased hepatic phospholipid and phosphatidylcholine levels and reduced phosphatidyl-ethanolamine N-methyltransferase activity even before the development of fibrosis. These effects were prevented or attenuated by supplementing the diet with 2.8 g/1000 kcal of a preparation rich in dilinoleoyl phosphatidylcholine, a highly bioavailable phosphatidylcholine species. There were significant (p < 0.001) correlations between phosphatidylethanolamine N-methyltransferase activity and both hepatic phosphatidylcholine (r = 0.678) and total phospholipid (r = 0.662). CONCLUSIONS: 1. Alcohol consumption diminishes phosphatidylethanolamine N-methyltransferase activity prior to the development of cirrhosis and decreases the hepatic content of its product, namely phosphatidylcholine, a key component of cell membranes. This may promote hepatic injury and possibly trigger fibrosis. 2. Phosphatidylcholine administration ameliorates the ethanol-induced decrease in phosphatidylethanolamine N-methyltransferase activity and corrects phospholipid and phosphatidylcholine depletions, thereby possibly contributing to the protection against alcoholic liver injury.
Animals↗
Tissue inhibitor of metalloproteinase is increased in the serum of precirrhotic and cirrhotic alcoholic patients and can serve as a marker of fibrosis.
One of the contributory factors to the development of cirrhosis is a decrease in collagenase activity, which may be related to levels of inhibitors such as serum tissue inhibitor of metalloproteinase. We therefore measured serum tissue inhibitor of metalloproteinase and serum procollagen III peptides (another proposed marker of fibrosis) in 16 healthy controls and 44 alcoholic patients with biopsy-proved liver disease, namely steatosis without fibrosis (n = 13), perivenular fibrosis (n = 10), septal fibrosis or cirrhosis or both (n = 15) and alcoholic hepatitis (n = 6). In alcoholic patients, serum tissue inhibitor of metalloproteinase values strongly correlated with fibrosis (rs = 0.70, p < 0.001). Compared with values in controls (177 +/- 12 ng/ml), serum tissue inhibitor of metalloproteinase was significantly elevated in perivenular fibrosis (330 +/- 22 ng/ml, p < 0.05), in septal fibrosis, cirrhosis or both (406 +/- 29 ng/ml, p < 0.001) and in alcoholic hepatitis (526 +/- 140 ng/ml, p < 0.001) but not in steatosis (204 +/- 17 ng/ml). In contrast, procollagen III peptides were significantly increased only in the septal fibrosis-cirrhosis group but not in the perivenular fibrosis group. With the threshold defined as the upper value of the steatosis group (resulting in a specificity of 100%), we found that serum tissue inhibitor of metalloproteinase was elevated in 50% of patients with perivenular fibrosis, in 87% of subjects with extensive fibrosis (septal fibrosis, cirrhosis or both) and in 67% of individuals with alcoholic hepatitis. The overall sensitivity of serum tissue inhibitor of metalloproteinase for detecting either perivenular fibrosis or more extensive fibrosis was 71%.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Differential depletion of carotenoids and tocopherol in liver disease.
Carotenoids and tocopherols are major natural protective agents against free radical-mediated liver damage, but their levels in diseased liver are largely uncharted. Therefore we carried out measurements with high-pressure liquid chromatography of alpha- and beta-carotene, lycopene, cryptoxanthin, lutein and zeaxanthin, total retinoids and alpha- and gamma-tocopherol. Liver tissue was obtained from percutaneous needle biopsies, livers of transplant recipients or a donor bank. Compared with controls (transplant donors; n = 13), levels of all carotenoids and retinoids were extremely low at all stages of liver disease. Patients with alcoholic cirrhosis (n = 11) had 20- and 25-fold decreases of levels of lycopene (p < 0.001) and alpha- and beta-carotene (p < 0.005), respectively. Even in subjects with less severe alcoholic liver disease (steatosis, perivenular fibrosis, portal fibrosis; n = 14) and in patients with nonalcoholic liver disease (n = 13), levels were four to six times lower than those in normal subjects. By contrast, levels of alpha-tocopherol were decreased significantly only in patients with cirrhosis, who displayed a threefold reduction. In the serum of most patients, lycopene and tocopherol concentrations were not depressed, whereas one third of alpha- and beta-carotene levels were low, probably reflecting poor dietary intake. A significant correlation was observed between serum and liver alpha- and beta-carotene levels (p < 0.0001; r = 0.715). However, of the patients with extremely low liver alpha- and beta-carotene concentrations, more than half had blood levels in the normal range, suggesting that liver disease interferes with the uptake, excretion or, perhaps, metabolism of alpha- and beta-carotene. In the cirrhotic livers of eight candidates for liver transplantation, the ratios of alpha- and beta-carotene to total retinoids and of beta-carotene to retinoids were much higher than those in normal livers, suggesting some impairment in the conversion of alpha- and beta-carotene to retinoids. In most cases, even with high ratios, absolute levels of hepatic alpha- and beta-carotene and retinoids were severely depressed. We concluded that, even in the presence of normal serum levels alpha- and beta-carotene, tocopherol and lycopene, patients with cirrhosis have extremely low hepatic levels.
Adult↗
Retinol forms retinoic acid via retinal.
Hepatic cytosol from normal deermice having cytosolic alcohol dehydrogenase (ADH+) also displays retinol dehydrogenase activity and converts retinol to retinoic acid, whereas cytosol from ADH- deermice lacks these enzyme activities and does not produce retinoic acid. Furthermore, microsomes from either strain do not convert retinol to retinoic acid. However, when cytosol from ADH- animals is added to the microsomes, retinoic acid is produced. The obligatory role of retinal as an intermediary step in retinoic acid formation is further shown by isotopic dilution of retinoic acid formed from labeled retinol upon addition of unlabeled retinal. Microsomal retinol dehydrogenase also catalyzes the reduction of retinal to retinol, thereby explaining the decrease in retinoic acid production from retinol in liver cytosol of ADH+ deermice when microsomes are added. Thus, the results of this study indicate that retinal is an obligatory intermediate in the hepatic production of retinoic acid from retinol and that cytosolic and microsomal retinol dehydrogenases play a key role in this process.
Alcohol Dehydrogenase↗
Polyunsaturated lecithin prevents acetaldehyde-mediated hepatic collagen accumulation by stimulating collagenase activity in cultured lipocytes.
We recently found that polyunsaturated lecithin prevents ethanol from causing cirrhosis in the baboon. Because transformation of lipocytes to transitional cells plays a key role in hepatic fibrogenesis in vivo, and because this process in alcohol-fed baboons was found to be attenuated by polyunsaturated lecithin, we focused on lipocytes to study the mechanism of the protective effect. Rat lipocytes cultured on plastic undergo spontaneous activation, accompanied by expression of alpha-smooth muscle actin isoform and production of substantial amounts of type I collagen. The latter was further increased on incubation with acetaldehyde. This in vitro model was used here to study how acetaldehyde-mediated collagen production and accumulation can be turned off. Addition of polyunsaturated lecithin (10 mumols/L) was found to prevent the acetaldehyde-induced increase in collagen accumulation by 83% (p less than 0.001). By contrast, a saturated phospholipid (10 mumols/L dilauroyl phosphatidylcholine), a monounsaturated one (10 mumols/L linoleoyl-palmitoyl phosphatidylcholine) or linoleic acid (20 mumols/L bound to albumin) had no such effect. Incorporation of [3H]proline into collagen and the expression of alpha-1 (I) procollagen mRNA were increased by acetaldehyde; the latter was not significantly affected by polyunsaturated lecithin. Polyunsaturated lecithin increased lipocyte collagenase activity by 100% (p less than 0.001), whereas dilauroyl phosphatidylcholine, linoleoyl-palmitoyl phosphatidylcholine and linoleic acid had no such action. We concluded that (a) polyunsaturated lecithin selectively prevents the acetaldehyde-induced increase in collagen accumulation in lipocyte cultures, whereas other phospholipids or linoleate have no such effect; and (b) polyunsaturated lecithin does not modify the acetaldehyde-mediated increase in alpha-1 (I) procollagen mRNA, but it increases collagenase activity, suggesting that the protective effect exerted by polyunsaturated lecithin against alcohol induced fibrosis in vivo is due at least in part to stimulation of collagenase activity, which may prevent excess collagen accumulation by offsetting increased collagen production.
Acetaldehyde↗
Interaction of ethanol with beta-carotene: delayed blood clearance and enhanced hepatotoxicity.
Because we had found that ethanol interacts with retinol, we investigated whether it also affects its precursor, beta-carotene. In 14 baboons fed ethanol (50% of total energy) for 2 to 5 yr with a standard amount of beta-carotene (one 200-gm carrot/day), levels of beta-carotene were much higher than in controls fed isocaloric carbohydrate, both in plasma (122.5 +/- 30.9 nmol/dl vs. 6.3 +/- 1.4 nmol/dl; p less than 0.005) and in liver (7.9 +/- 1.1 nmol/gm vs. 1.8 +/- 0.5 nmol/gm; p less than 0.001). Even 20 days after withdrawal of the carrots, plasma beta-carotene levels remained higher in alcohol-fed baboons than in controls (10.1 +/- 3.8 nmol/dl vs. less than 0.1 nmol/dl). Next, the diet was supplemented with beta-carotene beadlets: in four pairs of baboons given a low dose of beta-carotene (3 mg/1,000 kcal), plasma levels were significantly higher in alcohol-fed animals than in controls, even when expressed per cholesterol (although the latter increased with alcohol intake). Seven pairs of animals were given a higher dose (30 mg/1,000 kcal) of beta-carotene for 1 mo, followed, in four pairs, by 45 mg for another month. On cessation of beta-carotene treatment, plasma levels decreased more slowly in the alcohol-fed baboons than in the controls. Percutaneous liver biopsy specimens revealed that liver concentrations of beta-carotene correlated with plasma levels but were higher in the alcohol-fed baboons than in the control baboons, whereas the beta-carotene-induced increase in liver retinoids was lower (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon.
Chronic ethanol consumption by baboons (50% of energy from a liquid diet) for 18 to 36 mo resulted in significant depletion of hepatic S-adenosyl-L-methionine concentration: 74.6 +/- 2.4 nmol/gm vs. 108.9 +/- 8.2 nmol/gm liver in controls (p less than 0.005). The depletion was corrected with S-adenosyl-L-methionine (0.4 mg/kcal) administration (102.1 +/- 15.4 nmol/gm after S-adenosyl-L-methionine-ethanol, with 121.4 +/- 11.9 nmol/gm in controls). Ethanol also induced a depletion of glutathione (2.63 +/- 0.13 mumol/gm after ethanol vs. 4.87 +/- 0.36 mumol/gm in controls) that was attenuated by S-adenosyl-L-methionine (3.89 +/- 0.51 mumol/gm in S-adenosyl-L-methionine-methanol vs. 5.22 +/- 0.53 mumol/gm in S-adenosyl-L-methionine controls). There was a significant correlation between hepatic S-adenosyl-L-methionine and glutathione level (r = 0.497; p less than 0.01). After the baboons received ethanol, we observed the expected increase in circulating levels of the mitochondrial enzyme glutamic dehydrogenase: 95.1 +/- 21.4 IU/L vs. 13.4 +/- 1.8 IU/L; p less than 0.001, whereas in a corresponding group of animals given S-adenosyl-L-methionine with ethanol, the values were only 30.3 +/- 7.1 IU/L (vs. 9.6 +/- 0.7 IU/L in the S-adenosyl-L-methionine controls). This attenuation by S-adenosyl-L-methionine of the ethanol-induced increase in plasma glutamic dehydrogenase (p less than 0.005) was associated with a decrease in the number of giant mitochondria (assessed in percutaneous liver biopsy specimens), with a corresponding change in the activity of succinate dehydrogenase, a mitochondrial marker enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
Alanine Transaminase↗
Attenuation of alcohol-induced hepatic fibrosis by polyunsaturated lecithin.
Characteristic features of alcoholic liver injury include fibrosis and striking membrane alterations, with associated phospholipid changes. To offset some of these abnormalities, a 10-yr study was conducted in baboons: 12 animals (eight females, four males) were fed a liquid diet supplemented with polyunsaturated lecithin (4.1 mg/kcal) for up to 8 yr, with either ethanol (50% of total energy) or isocaloric carbohydrate. They were compared with another group of 18 baboons fed an equivalent amount of the same diet (with or without ethanol), but devoid of lecithin. In the two groups, comparable increases in lipids developed in the ethanol-fed animals, but striking differences in the degree of fibrosis were seen. Whereas at least septal fibrosis (with cirrhosis in two) and transformation of their lipocytes into transitional cells developed in seven of the nine baboons fed the regular diet with ethanol, septal fibrosis did not develop in any animals fed lecithin (p less than 0.005). They did not progress beyond the stage of perivenular fibrosis (sometimes associated with pericellular and perisinusoidal fibrosis) and had a significantly lesser activation of lipocytes to transitional cells. Furthermore, when three of these animals were taken off lecithin, but continued on the same amount of the ethanol-containing diet, they rapidly (within 18 to 21 mo) progressed to cirrhosis, accompanied by an increased transformation of their lipocytes to transitional cells. These results indicate that some component of lecithin exerts a protective action against the fibrogenic effects of ethanol. Because we had previously found that choline, in amounts present in lecithin, has no comparable action, the polyunsaturated phospholipids themselves might be responsible for the protective effect.
Animals↗
NAD(+)-dependent retinol dehydrogenase in liver microsomes.
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Alcohol Oxidoreductases↗
Interaction of ethanol with enflurane metabolism and toxicity: role of P450IIE1.
Administration of enflurane (EF), a widely-used anesthetic agent, sometimes results in occult liver injury. As hepatic cytochromes P450 oxidize EF to a reactive intermediate, we assessed whether one such microsomal enzyme, ethanol-inducible P450IIE1, plays an obligatory role in EF metabolic activation and hepatotoxicity. Liver microsomes from rats fed ethanol (36% of total calories for 14 days) oxidized 1 mM EF (measured by its defluorination) at rates nearly 10-fold greater than those from control rats, reflecting the markedly enhanced content of immunoreactive microsomal P450IIE1 in the former animals. P450IIE1 involvement in hepatic EF oxidation was further suggested by the pronounced inhibition of microsomal defluorination noted with P450IIE1 antibodies and with ethanol, a specific substrate for this enzyme. EF administration to rats treated chronically with ethanol caused significant elevations in plasma levels of aspartate and alanine aminotransferases and glutamate dehydrogenase, indicative of hepatic injury, whereas concurrent treatment of naive rats with EF and ethanol failed to produce the same effect. Our results imply that ethanol-inducible P450IIE1 is the primary catalyst of hepatic EF bioactivation and that the increased bioactivation occurring in vivo secondary to chronic ethanol consumption is attendant with an increased incidence of EF hepatotoxicity.
Animals↗
Metabolism of retinol and retinoic acid by human liver cytochrome P450IIC8.
Liver microsomes obtained from nine subjects were found to metabolize retinol to polar metabolites, including 4-hydroxyretinol. In a reconstituted monooxygenase system containing human liver P450IIC8, retinol was converted to 4-hydroxyretinol and other polar metabolites, with a Km of 0.071 mM and a Vmax of 1.73 nmol/min/nmol P450. Neither P450IIC9 nor P450IIE1, two other purified human P450s, displayed significant retinol hydroxylase activity. Immunoblots performed with a monospecific antibody directed against human P450IIC8 revealed that appreciable amounts of this enzyme were present in human liver microsomes. The same antibody significantly inhibited retinol metabolism in liver microsomes and in the system reconstituted with P450IIC8. The system reconstituted with P450IIC8 also converted retinoic acid to polar metabolites. Thus, this study shows, for the first time, metabolism of two physiologic substrates by a human liver cytochrome P450 related to a group of "constitutive" rodent P450s believed to participate in the metabolism of endogenous compounds. Through its involvement in vitamin A metabolism, P450IIC8 may participate in maintaining the balance between those vitamin A concentrations that promote cellular integrity (and oppose the development of cancer) and those concentrations that cause cellular toxicity.
Adult↗
Increased hepatic retinal dehydrogenase activity after phenobarbital and ethanol administration.
Cytosolic retinal dehydrogenase (EC 1.2.1.36, retinal: NAD+ oxidoreductase) activity was measured by assessing the conversion of retinal to retinoic acid by HPLC. In vitro, acetaldehyde, chloral hydrate and disulfiram were found to be inhibitors, whereas 95% of the activity remained in the presence of cyanide or in the absence of oxygen. In rats, retinal dehydrogenase activity prevailed over that of retinal oxidase. By contrast, in deermice, 80% of retinal oxidation was due to the oxidase rather than the retinal dehydrogenase activity in a normal strain (ADH+) as well as in one lacking alcohol dehydrogenase (ADH-). In ADH- deermice, retinal oxidase activity was greater than in ADH+ animals. In vivo, in the rat, chronic ethanol administration resulted in a significant increase of the dehydrogenase activity in the liver, but not in other tissues. After phenobarbital administration, hepatic retinal dehydrogenase activity was increased 8-fold, but no extrahepatic induction was observed. Conversely, feeding rats with a diet devoid of the precursor for the substrate (retinal) by replacing retinyl acetate with an equivalent amount of retinoic acid resulted in decreased retinal dehydrogenase activity. Under conditions in which retinal dehydrogenase activity is rate-limiting for the metabolism of retinal to retinoic acid, its induction after phenobarbital or ethanol administration may contribute to hepatic vitamin A depletion.
Aldehyde Oxidoreductases↗
Role of vitamin A degradation in the control of hepatic levels in the rat.
The relationship between excess vitamin A intake and accumulation in various tissues, including the liver, was studied in rats fed for 45 d four levels of vitamin A: 1, 6, 30 and 100 IU/kcal. As vitamin A intake increased, progressively smaller fractions of the administered vitamin A were recovered in tissue. The decrease in fractional recovery in the tissues examined was calculated from the differences between intake, tissue level and excretion, and was found to increase after administration of high vitamin A diets. This could be explained, at least in part, on the basis of an enhanced rate of vitamin A degradation as a function of the increased concentration of retinol in the liver. At high tissue retinol concentrations, calculated rates of retinol metabolism via the hepatic cytosolic retinol dehydrogenase (EC 1.1.1.1) and the recently discovered microsomal retinol dehydrogenase and oxidase vastly exceeded the decrease in fractional recovery of vitamin A accumulation in the tissues. This calculated rise in metabolic rate was verified by a corresponding increase in urinary polar metabolites derived from labeled retinol. Thus, accelerated catabolism as a function of increased hepatic vitamin A concentration may provide a homeostatic mechanism which offsets in part excessive vitamin A accumulation.
Administration, Oral↗
Combined effects of protein deficiency and chronic ethanol consumption on rat pancreas.
This study was performed in order to delineate the combined effects of protein deficiency and chronic ethanol ingestion on the rat pancreas. Rats fed ethanol in combination with protein-deficient diets developed marked steatosis, whereas alcohol ingestion with nutritionally adequate diets and protein deficiency alone each were associated with a more moderate degree of pancreatic lipid accumulation. On biochemical analysis, it was found that protein deficiency decreased pancreatic phospholipid content. Furthermore, both protein deficiency and chronic ethanol consumption increased pancreatic cholesteryl ester content, and their effects were additive. Functional changes were studied using isolated pancreative acini. Protein deficiency depressed the tissue content of lipase and the ability of pancreatic acini to secrete lipase. Chronic ethanol feeding increased lipase levels in the acini and also their secretory capacity. Thus, to the extent that enzyme accumulation in the pancreas plays a role in the pathogenesis of alcoholic pancreatitis, these results may explain the higher incidence of pancreatitis in well-nourished alcoholics that has been documented in dietary surveys.
Alcoholism↗