FACTORS AFFECTING HEPATIC MICROSOMAL ENZYME SYSTEMS INVOLVED IN DRUG METABOLISM.

Abstract

Abstract The activity of certain hepatic microsomal enzymes which metabolize drugs is not constant. These enzyme activities can be affected by drugs, disease states and certain alterations in cellular environment which need not lead to recognizable hepatic pathology. Microsomal drug metabolizing enzyme activity can be increased above normal levels by treatment of animals with a variety of drugs (e.g. phenobarbital, chlordan) which appear to stimulate the synthesis of new enzyme protein. Absence or abnormally low levels of microsomal drug metabolizing enzyme activity are seen in fetal and newborn animals, in mice starved 48–72 hr, in rabbits suffering obstructive jaundice, in rats treated 48–72 hr previously with alloxan, in hepatic tissue remaining after partial hepatectomy, and in a variety of drug-induced and/or transplantable hepatomas (e.g. Novikoff, Morris 5123). Changes which often accompany these alterations in the rate of microsomal drug metabolism include, (1) loss of hepatic glycogen when drug metabolism slows down and increased glycogen levels when drug metabolism speeds up, and (2) loss or decrease in amount of smooth-surfaced ergastoplasm (SSE) when drug metabolism is depressed and proliferation of SSE when metabolism is increased. Other studies have shown that several microsomal drug-metabolizing enzymes are localized predominantly in smooth-surfaced microsomes which are derived presumably from SSE. Predictions of the level of microsomal drug-metabolizing enzyme activity are best made from the amount of SSE in the hepatic parenchymal cell since hepatic glycogen levels can be changed (e.g. by epinephrine injections) without changing microsomal enzyme activity.