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MARÍA JOSÉ GÓMEZ-LECHÓN y MARÍA TERESA DONATO AN. R. ACAD. NAC. FARM.

DRUG-INDUCED HEPATIC INJURY

Substances capable of producing liver damage and, more
specifically, hepatocyte damage are known as hepatotoxins. Intrinsic
hepatotoxins are substances that exert their effects in all individuals,
in a dose-dependent and hence predictable manner. These toxins
can interfere directly with cell metabolism (active hepatotoxins) (50)
or become toxic once they have been biotransformed (latent
hepatotoxins). Idiosyncratic hepatotoxicity, on the other hand, may
be the consequence of an abnormal metabolism of the drug by
susceptible individuals (metabolic idiosincrasy) or be elicited by an
immune-mediated hepatocyte injury (allergic hepatitis). The former
has a geno- or phenotypic basis that results in the over/under
expression of drug metabolizing enzymes, a different drug
metabolism pattern and eventually the abnormal production of a
toxic metabolite. This type of idiosyncratic toxicity is dose-dependent
in susceptible individuals. Idiosyncratic drug toxicity is a rare
human-specific event and therefore not detectable in experimental
animals and impossible to be studied in clinical trials (51). Some
xenobiotics are electrophilic in nature, and others are bioactivated
by the liver to highly reactive metabolites generally more toxic than
the parent compound, which is the key to many toxic phenomena
(50, 52, 53). To minimize these effects, hepatocytes have effective
defence mechanisms, and ultimately it is the balance between
bioactivation, detoxification and defence/repair mechanisms that
determines whether a compound will or will not elicit a toxic effect.

Figure 4 summarizes the molecular events that can be involved in
hepatocyte toxicity: 1) The impairment of the biochemical functions
of hepatocytes by the drug or by any of its stable metabolites is
the first possible mechanism of hepatotoxicity (52-54). 2) The
mitochondrion is a frequent target of hepatotoxic drugs and the
alteration of its function has immediate effects on the energetic
balance of cells (54). Depletion of ATP is, in fact, an early event in
the course of drug-induced toxicity that precedes the irreversible
stages of cell injury (56). 3) Lipid peroxidation. It is a free radical
process leading to the oxidative degradation of lipids that finally
may disrupt the structure and functionality of the cell membranes
(56). 4) Alteration of intracellular Ca2+ concentration. Intracellular

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