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.

Abstract

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 ...

Distribution of nitric oxide synthase in normal and cirrhotic human liver

“…The hepatic enzymes mediating the glucagon-sensitive glucose-forming pathways and the urea cycle exemplify the concept of metabolic zonation (21). The pathological significance of hepatocyte heterogeneity is best illustrated by the observation that there is zonal sensitivity of hepatocytes to toxic damage by hypoxia and hepatotoxins, including acetaminophen, halothane, CCl 4 , and bromobenzene (23,24).…”

Regulation of oxygen consumption and microcirculation by α‐sympathetic nerves in isolated perfused rat liver

“…At the end of the experiments, the electrodes were calibrated on the surface of the liver fixed with 1% formaldehyde by perfusing the fixed liver with medium equilibrated with 95% N2/5% CO2 or 95% 02/5% COZ. The sensitivity of the 02 electrode was reduced 2-to 3-fold when placed on the liver surface as compared to the sensitivity determined in a saline solution [13,15].…”

“…Therefore the purpose of the present investigation was to study in the perfused rat liver the effect of sympathetic nerves on oxygen consumption, on microcirculation and on tissue oxygen tension in periportal and perivenous areas of surface acini, which has become possible with the recent development of miniature oxygen electrodes [13].…”

Dynamic Adaptation of Liver Mitochondria to Chronic Alcohol Feeding in Mice

“…The liver adapts to alcohol and develops an enhanced capacity to metabolize alcohol following feeding (13,16,17). This enhanced capacity to metabolize alcohol is associated with increased oxygen uptake by the liver (13,18,19), suggesting that there is greater mitochondrial respiration in these hepatocytes. ADH and ALDH2 levels do not change with alcohol feeding, suggesting that adaptation to alcohol occurs through mitochondrial alterations or other pathways (15)(16)(17).…”