Page 350 - The Toxicology of Fishes

330 The Toxicology of Fishes

Major Functions of the Liver
The three major functions of the liver essential for life of the organism are:

• Uptake, metabolism, storage, and redistribution of nutrients and other endogenous mole-
cules—The synthetic and excretory functions of the liver maintain the homeostasis of the
organism. To achieve this, specific molecules are synthesized in hepatocytes, packaged in the
Golgi apparatus, transported in a specific direction for release into the intercellular spaces and
to the bloodstream, where they are taken up by other organs and utilized. Some examples of
storage, synthesis, and redistribution functions include glycogenolysis and hepatocyte release
of glucose to govern blood glucose levels; hormone synthesis and release (e.g., somatomedins);
synthesis and release of proteins, as in the case of serum albumins, the yolk precursor vitello-
genin, and the zona radiata protein or choriogenin. The removal, metabolism, and eventual
excretion of compounds also participate in the homeostatic role of the liver; for instance,
hormones are taken up and broken down by the liver.
• Metabolism of lipophilic compounds, including xenobiotics—Biotransformation reactions cat-
alyze the conversion of endogenous as well as exogenous compounds with poor water solubility
to more hydrophilic metabolites that can be readily excreted. With respect to xenobiotics, the
majority of hepatic biotransformation reactions may be considered as a detoxification process
decreasing toxic body burden by enhancing excretion. However, during the biotransformation
process, generation of electrophilic reactive species can lead to interaction with basic cellular
constituents such as DNA and proteins. The end result of this process may be disruption of
normal cellular function and overt toxicity, including acute forms and chronic states such as
carcinogenesis and tumor formation.
• Formation and excretion of bile—Bile excretion is important for the elimination of degradation
products of endogenous compounds such as heme or steroid hormones, as well as for the
elimination of xenobiotics and their metabolites and some metals such as copper and mercury.

All of these hepatic functions—synthesis and redistribution of nutrients and intermediary metabolites,
biotransformation, and bile formation—have been shown to be involved not only in physiological states
but also in processes leading to alterations in hepatic morphology and physiology. It is this great metabolic
capacity of the liver that makes it both a target and an organ of defence. When toxic hits on the target
occur, they may lead to alterations or injury in liver structure and function. Because of the multiple
physiologic functions of the liver and its considerable plasticity, the liver responds to toxic insults in
many different ways; thus, there appears to be no prototype single reaction classification of hepatotoxicity.
Rather, a combination of morphologic pattern, functional alteration, and mechanisms is used to classify
hepatotoxicants in mammals (Vandenberghe, 1996) and could be used for fishes as well.
The deterioration of hepatic structure and function not only is relevant for the liver itself but may also
lead to aberrations in other organs and to death of the organism. Loss of biliary function alone is
incompatible with life. Hepatic clearance function and dysfunction involving the microvasculature and
the intrahepatic biliary system for excretion of compounds as well as the pronounced metabolic capacity
of this organ may all play a role in the spectrum of toxic conditions possible in this organ. The liver
also possesses a pronounced capacity to acclimate to toxic stress, producing protective molecules or
performing efficient repair and full or partial recovery. The latter may be considered acclimation,
providing for survival of the altered host.
An understanding of chemical hepatotoxicity requires an appreciation of anatomic and physiologic
features of the liver. With respect to fish liver, it is important to emphasize that, although fish and
mammalian liver agree in many features, there are still differences that may influence chemical toxicity
and especially its interpretation. Also, although there are basic similarities of structure and function
common to the fraction of the total fish species that have been investigated, species differences must
always be considered, and this should involve considerations at all levels of biological organization.