1. ENVR 430 Hepatic Physiology and Toxicology Nov 13, 2006 Jane Ellen Simmons, 919-541-7829 Simmons.Jane@epa.gov

2. I.General Information A. Size and Location The liver is the largest internal organ, in both animals and humans. In humans, the liver is: ~2.5 % of body weight in adults ~ 5% of body weight at birth The adult human liver weighs 1,500 gm ± 100 gm, males 1,300 gm ± 100 gm, females

3. In humans, the liver is a single organ divided into four distinct lobes: right lobe left lobe quadrate lobe caudate lobe Location: upper part of the abdomen. Upper margin at the level of the 5th rib; lower margin lies slightly below the rib cage on the right side of the body. The ribs provide mechanical protection of the liver from physical damage.

4. II. Hepatic Regeneration The liver has a remarkably high capacity for regeneration. After hepatectomy (excision or removal of part of the liver), the human liver rebuilds itself at a rate of up to 100 gm/day. Up to 80% of the liver can be removed with no permanent impairment of liver function How does the liver regenerate? Two adaptive responses are used: a) hypertrophy - increase in cell size b) hyperplasia - cellular proliferation (increase in cell number)

5. II. The Liver as a Target Organ Factors that make the liver a common target for environmental chemicals and pharmaceutical agents. a) High metabolic capacity. The liver has a high concentration, relative to other organs, of xenobiotic- metabolizing enzymes, for example, the cytochrome P-450 monooxygenase system. b) Uptake and Concentration. The liver tends to concentrate compounds because: 1) Diffusion into hepatocyte enabled. The 'design' of the sinusoidal lining cells (thin, fenestrated epithelium) provides close contact between the chemicals carried in the blood and the hepatocytes. 2) Hepatocytes have a high concentration of membranes, increasing the ability to concentrate lipophilic compounds.

6. 3) Chemicals may be concentrated in the liver due to the presence (concentration) of sinusoidal transporters that increase the hepatic extraction of the compounds carried by these transporters. c) Biliary secretion. a) Compounds eliminated by bile secretion can reach high concentrations in the liver. Examples include such metals as arsenic, copper, manganese, cadmium, selenium, gold and silver. b) Enterohepatic circulation can lead to high hepatic concentrations of chemicals Examples of compounds that undergo enterhepatic circulation: bile salts, bile pigments, cholesterol, kepone and arsenic

8. d) Location of the liver and its Blood Supply Oral Route of Exposure. For those chemicals with an oral route of exposure, the hepatic blood supply leads to high exposure. Absorption from the GI tract into blood that flows into the portal vein, which perfuses the liver, leads to the liver being the first organ perfused by chemicals absorbed from the gut. Inhalation Exposure. The liver is highly perfused, receiving 20-25% percent of total cardiac output. Although much of this (~80%) is from portal perfusion (blood that goes to the liver from the heart via passage first through other GI tract organs), the remaining 20% is from 'direct' cardiac perfusion.

9. IV. Portal Blood System The hepatic blood supply makes the liver particularly susceptible to toxic chemicals, because of a) its high rate of perfusion and b) the 'pass-through' the liver of the venous blood draining other GI tract organs. The liver receives between 1/4 and 1/5 of total cardiac output; this equal about 1500 ml/min in a 70 kg human. The liver receives both arterial and venous blood. The arterial blood enters the liver via the hepatic artery while the venous blood enters the liver via the portial vein The hepatic artery is a branch of the celiac trunk which branches off from the aorta.

10. The portal vein is the venous drainage of a number of different gastrointestinal structures, including: esophagus stomach spleen pancreas small intestine colon PressureBlood FlowOxygen Hepatic artery 120 mmHg300 ml/min 20 ml/min Portal Vein 8-10 mmHg1200 ml/min 40 ml/min

14. Advantages (and Disadvantages) of a portal system of blood delivery to the liver A. Cleaning of the blood. The gut wall is leaky and micro- organisms (both endogenous and exogenous) pass fairly freely into the portal blood stream. These micro-organisms are removed from the blood, before they reach the systemic circulation, by passage through the liver. B.Nutrient buffering. Approximately 2/3 of the total glucose entering the liver via the portal vein is extracted by the liver, then stored, and released to the systemic circulation as needed. Approximately 1/2 of the protein entering the liver via the portal vein is removed by the liver, buffering the protein concentration of the systemic circulation.

15. C.Xenobiotic metabolism. A double-edged sword. When the parent compound is the toxic moiety, metabolism often leads to a decrease in the toxic potency.

16. When a metabolite is the toxic moiety, metabolism often leads to an increase in toxic potency.

17. V. Cell Types Hepatocytes Bile Duct Cells Endothelial Cells Kupffer Cells Ito Cells Pit Cells

18. VI. Organizational/Functional Units of the Liver The relationship of hepatic cells, blood supply, blood flow, biliary system flow. A. Hepatic Lobule (Classical Structure ) Three Areas of the Lobule 1. centrilobular / centrizonal / central 2. midzonal 3. periportal / peripheral Location and/or direction of: cells (hepatocyte, bile duct cell, endothelial cell [aka sinusoidal lining cell], Kupffer cell, Ito cell, Pit cell), central vein (terminal hepatic venule), portal triad (terminal hepatic artery, terminal hepatic vein, bile duct), sinusoid, blood flow, bile flow

19. Liver Lobule

22. B. Liver Acinus Three Areas of the Acinus Zone 1 (rough match with periportal area of the lobule) Zone 2 (rough match with midzonal area of lobule) Zone 3 (rough match with centrilobular area of lobule) Location and/or direction of: cells (hepatocyte, bile duct cell, endothelial cell [aka sinusoidal lining cell], Kupffer cell, Ito cell, Pit cell), central vein (terminal hepatic venule), portal triad (terminal hepatic artery, terminal hepatic vein, bile duct), sinusoid, blood flow, bile flow

27. VI. C. Comparison of the Centrilobular and Periportal Areas Centrilobular (Zone 3) Periportal (Zone 1) (Relative to Periportal)(Relative to Centrilobular) dec. O2 (30-40 mm Hg, 4-5% O2)incr. O2 (~65 mm Hg, 9-13% O2) dec. nutrientsincr. nutrients dec. xenobiotic concincr. xenobiotic conc incr. P450dec. P450 incr. P450IIE1 (cyp 2E1)dec. P450IIE1 (cyp 2E1) dec. ALTincr. ALT dec. alcohol dehydrogenaseincr. alcohol dehydrogenase dec. bile saltsincr. bile salts dec. mitochondriaincr. Mitochondria (fatty acid oxidation, (fatty acid oxidation, gluconeogenesis gluconeogenesisammonia detox) dec. glutathioneincr. glutathione dec. Kupffer cells #incr. Kupffer cells #