Functional heterogeneity among liver cells: implications for drug toxicity and metabolism

Most drugs and chemicals that are toxic to the liver cause selective damage to liver cells surrounding terminal branches of hepatic veins. Recent work has emphasized the role of metabolic activation in such toxicity. The hepatic mixed function oxygenases, with cytochrome P450 as terminal oxidase, mediate metabolic activation so that selective toxicity provides circumstantial evidence that MFO activity is also concentrated around hepatic veins. However, the picture is probably more complex. Within the liver acinus heterogeneity of oxygen tension, rates of protein synthesis, protective hydrolytic and conjugating enzymes, and concentration of the protective nucleophile, glutathione, exist. The challenge facing the experimentalist is to isolate these processes for study without destroying the anatomical basis for heterogeneity.