ABSTRACT
Historically, the fate of a drug and its adverse effects in the body were estimated based on the
established rules of toxicokinetics and toxicodynamics. It was observed that drugs and toxic
chemicals follow the rules of absorption, distribution, metabolism, and excretion (1). Often,
central to the pharmacological actions of many drugs was their phase I metabolism mediated
by the drug-biotransforming enzymes, such as cytochrome P450 and others. After the drugs are
absorbed and distributed in the body, they undergo metabolism via a combination of
phase I and II biotransforming enzymes to generate water-soluble metabolites, which would
be easily excreted from the body (2). However, it was observed that metabolism of drugs and
toxicants may also lead to generation of highly reactive metabolites and free radicals which
attack cellular macromolecules and inflict cell and tissue injury (2). While this is widely
accepted as a generalized mechanism of initiation of liver injury, it was understood that
continuation or progressive expansion of injury occurs through other mechanisms, these
mechanisms have largely remained obscure until recently (3-6). Liver is the main site of
drug and toxicant metabolism since the hepatocytes are a reservoir of microsomal and cytosolic
phase I and II drug-metabolizing enzymes (2). This has made liver a prime target for drug-and
toxicant-induced injury. The degree of liver injury was thought to be proportional to the
generation of reactive metabolites of the drugs or toxicants via drug-metabolizing enzyme-
mediated bioactivation. It is now known that such oversimplified concepts overlook the
imposing effects of biological responses to toxic injury which control the final toxic outcomes.
Very little was known about the opposing toxicodynamic response of tissue repair following
chemical-induced liver injury (7-9).
