The swift increase in alcohol metabolism

Yuki, Takehiko; Israel, Yedy; Thurman, Ronald G.

doi:10.1016/0006-2952(82)90536-6

Cited by 39 publications

(14 citation statements)

References 23 publications

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“…6-Propyl-2-thiouracil prevents hypoxia-induced pericentral necrosis in livers from ethanol-treated rats (3) and also inhibits the "swift increase in alcohol metabolism" syndrome (37). We found that treatment ofrats with 6-propyl-2-thiouracil abolished both the increase in tissue respiration and the enhanced pericentral oxygen gradient in perfused livers caused by chronic ethanol treatment (Table 2).…”

Section: Methodsmentioning

confidence: 55%

Periportal and pericentral pyridine nucleotide fluorescence from the surface of the perfused liver: evaluation of the hypothesis that chronic treatment with ethanol produces pericentral hypoxia.

Ji¹,

Lemasters²,

Christenson³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

139

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Pyridine nucleotide fluorescence made from the surface of the hemoglobin-free perfused rat liver was measured continuously by using a "micro-light guide" placed on selected periportal and pericentral regions of the liver lobule. From the portal oxygen tension at which pyridine nucleotide reduction first occurred in pericentral regions, the oxygen gradient across the liver lobule was estimated in livers from rats treated chronically with ethanol or sucrose. Chronic treatment with ethanol increased the average lobular oxygen gradient from 275 to 400 torr (1 torr = 133 Pa), primarily due to the increase in the oxygen gradient in pericentral regions. Ethanol treatment also increased hepatic oxygen uptake significantly, from 110 to 144 (Iumol/g)/hr. Treatment with the antithyroid drug 6-propyl-2-thiouracil reversed the effect of ethanol on 02 uptake and on the lobular oxygen gradient. The oxygen gradients measured with the micro-light guide were confirmed by direct measurement oftissue oxygen tensions in periportal and pericentral areas by using an oxygen electrode. These data are consistent with the hypothesis that chronic treatment with ethanol causes the pericentral region of the liver lobule to become susceptible to hypoxic cellular injury. This may be responsible, at least in part, for the localized hepatotoxic effects of ethanol.Ethanol-induced liver damage is often confined to the pericentral region of the liver lobule (1-3). Israel et al. (3) have postulated that ethanol-induced pericentral necrosis results from an accentuated gradient of decreasing oxygen tension from the portal to the central venous end of the sinusoid leading to pericentral hypoxia. This hypothesis is based on the observations that ethanol treatment increased the rate of oxygen uptake in liver slices (4-6) and perfused liver (7,8). In support of this postulate, Israel et aL (3) demonstrated that, after brief exposure to hypoxia, pericentral necrosis was greater in ethanol-treated rats than in controls. Treatment ofrats with the antithyroid drug 6-propyl-2-thiouracil abolished the ethanol-induced increase in liver respiration and diminished the tissue damage produced by hypoxia (3).We have used a "micro-light guide" fluorometric technique (9-12) to test this hypothesis directly. This technique allows continuous measurement of pyridine nucleotide fluorescence from the periportal or pericentral regions of the perfused liver. Chance and co-workers (13, 14) have shown that tissue pyridine nucleotide fluorescence can be used to monitor intracellular oxygen tension indirectly because pyridine nucleotide fluorescence increases when tissue oxygen tension falls below the level (<1 torr; 1 torr = 133 Pa) necessary to satisfy the oxygen requirement of mitochondrial cytochrome oxidase. By measuring the oxygen tension in the influent perfusate at which pyridine nucleotide fluorescence begins to increase in pericentral regions, it is possible to estimate the oxygen gradient across the liver lobule. The results of the present study indicate that ...

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Section: Methodsmentioning

confidence: 55%

Periportal and pericentral pyridine nucleotide fluorescence from the surface of the perfused liver: evaluation of the hypothesis that chronic treatment with ethanol produces pericentral hypoxia.

Ji¹,

Lemasters²,

Christenson³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

139

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“…PTU has been used both experimentally and clinically because it reduces the increase in oxygen consumption induced by acute or chronic ethanol intake (1,6). However, the possibility of PTU also having a direct effect on liver blood flow has not been explored.…”

mentioning

confidence: 99%

Effects of propylthiouracil and methimazole on splanchnic hemodynamics in awake and unrestrained rats

Kawasaki¹,

Carmichael²,

Giles³

et al. 1989

Hepatology

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The treatment of alcoholic liver disease with propylthiouracil is based on its effect of suppressing the ethanol-induced increase in hepatic oxygen consumption. It has been postulated that liver necrosis ensues when the increase in oxygen demand by the liver exceeds oxygen delivery to this organ. Data are now presented which show that propylthiouracil also increases portal blood flow in awake, unrestrained rats. Liver blood flow was determined using the labeled microsphere technique in rats at various intervals (0.25, 0.5, 1.0, 3.0, 6.0 and 24 hr) after oral propylthiouracil (50 mg per kg). Administration of propylthiouracil (dose range: 6.25 to 100.0 mg per kg) produced a dose-dependent increase in portal blood flow when given either orally or intraarterially. Maximal flows were obtained with 50 mg per kg (controls = 37.8 +/- 1.5, oral propylthiouracil = 50.7 +/- 2.2 ml.kg-1.min-1). This increase in portal blood flow was accompanied by a decrease in preportal vascular resistance (controls = 2.61 +/- 0.16; propylthiouracil, 50 mg per kg = 1.79 +/- 0.09 mmHg per ml.kg-1.min-1). These effects were correlated with the plasma concentrations of propylthiouracil (r = 0.67, n = 68, p less than or equal to 0.001). The effect of oral propylthiouracil (50 mg per kg) on portal blood flow started at 0.5 hr and lasted for 6 hr after administration, whereas total liver blood flow was increased for 3 hr. Oral propylthiouracil (50 mg per kg) for 5 days resulted in a 53% increase in thyroid weight, an 85% reduction in 125I thyroid uptake and a 74% decrease in serum thyroxine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Moreover, nimodipine attenuated the Swift Increase in Alcohol Metabolism (SIAM). 29 It has been reported necrosis were reduced significantly by nimodipine ( Fig. 6A and C); however, there was only a tendency for inflammation that Ca 2/ channel blockers prevent liver injury caused by hypoxia 12,13 as well as by several hepatotoxic agents, such as to be reduced because of variability in this parameter (Fig.…”

Section: Discussionmentioning

confidence: 87%

“…Alcohol-induced liver dis-ment with ethanol also causes a very rapid increase in hepatic respiration and ethanol metabolism (SIAM). 29 This ease resulting from the excess consumption of alcoholic beverages affects millions of patients worldwide and is the fourth increase in oxygen uptake caused by a hypermetabolic state 29 may cause centrilobular hypoxia and lead to pericentral liver major cause of death in men in the urban United States. 48 Unfortunately, treatment efforts are ineffective, in part be-injury.…”

Section: Discussionmentioning

confidence: 99%

Nimodipine, A Dihydropyridine–Type Calcium Channel Blocker, Prevents Alcoholic Hepatitis Caused by Chronic Intragastric Ethanol Exposure in the Rat

et al. 1996

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It has been shown recently that inactivation of Kupffer cells prevents free radical formation and early alcohol-induced liver injury, and that hypoxia subsequent to a hypermetabolic state caused by activated Kupffer cells is likely involved in the mechanism. Calcium is essential for the activation of Kupffer cells, which contain L-type voltage-dependent Ca2+ channels. Therefore, the purpose of this study was to determine whether a Ca2+ channel blocker, nimodipine, prevents early alcohol-induced liver injury in vivo and to evaluate its effect on intracellular calcium ([Ca2+]i) in Kupffer cells in vitro. Male Wistar rats were exposed to ethanol (10-12 g/kg/d) continuously for up to 4 weeks via intragastric feeding using an enteral model developed by Tsukamoto and French. In this model, ethanol causes steatosis, necrosis, and inflammation in only a few weeks. In the experimental group, nimodipine (10 mg/kg/d) was added to the diet and was shielded from direct light. Nimodipine had no effect on body weight over a 4-week treatment period, nor were mean ethanol concentrations or their cyclic pattern in urine affected. The mean urine ethanol values were 154 +/- 11 mg/dL in ethanol-fed and 144 +/- 38 mg/dL in ethanol + nimodipine-fed rats. After 4 weeks, serum aspartate transaminase (AST) levels were elevated in ethanol-treated rats to 183 +/- 78 U/L. In contrast, values only reached 101 +/- 9 U/L in rats given nimodipine + ethanol-values which were significantly lower. Steatosis and necrosis assessed histologically were also reduced significantly by nimodipine. Nimodipine (10 micrograms/kg) also blocked the swift increase in alcohol metabolism and elevated oxygen consumption in perfused livers from rats treated with alcohol in vivo. Further, in cultured Kupffer cells, nimodipine (1 mumol/L) largely prevented the elevation in [Ca2+]i caused by lipopolysaccharide (LPS) (LPS, 200 +/- 11 nmol/L; LPS + nimodipine, 94 +/- 31 nmol/L; P < .05). These results indicate that nimodipine prevents alcoholic hepatitis, possibly by inhibition of endotoxin-mediated Kupffer cell activation.

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The swift increase in alcohol metabolism

Cited by 39 publications

References 23 publications

Periportal and pericentral pyridine nucleotide fluorescence from the surface of the perfused liver: evaluation of the hypothesis that chronic treatment with ethanol produces pericentral hypoxia.

Periportal and pericentral pyridine nucleotide fluorescence from the surface of the perfused liver: evaluation of the hypothesis that chronic treatment with ethanol produces pericentral hypoxia.

Effects of propylthiouracil and methimazole on splanchnic hemodynamics in awake and unrestrained rats

Nimodipine, A Dihydropyridine–Type Calcium Channel Blocker, Prevents Alcoholic Hepatitis Caused by Chronic Intragastric Ethanol Exposure in the Rat

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