Short communication

Hepatic drug metabolism in vitro in the horse

The apoprotein expression and the catalytic activities of cytochrome P450s involved in the biotransformation of xenobiotics were investigated in horse liver microsomes and compared with those of food producing (cattle, pigs, broiler chicks, and rabbits) and laboratory species (rats). Western blot analysis revealed the presence of proteins immunorelated to rat CYP 1A, CYP 2B, CYP 2E, and CYP 3A subfamilies in hepatic microsomes from horses and from any other examined species. With the exception of the N-demethylation of N-nitrosodimethylamine in broiler chicks, all the recorded interspecies differences were quantitative in nature. Equine preparations proved the most active in the biotransformation of the CYP 1A substrates ethoxy- and methoxyresorufin and the least active in the metabolism of aminopyrine and ethoxycoumarin. On a comparative basis, large differences were observed in the rate of the in vitro metabolism of model substrates between “minor” (rabbits, horses) and “major” food producing species. Taken in due consideration the limitations of the in vitro approach, results from this study reinforce the conclusion that studies on drug efficacy and residue depletion should be performed in each target species.

After coming in contact with living organisms, the majority of foreign compounds undergo a number of chemical reactions known as biotransformations. These are performed by hepatic and extra-hepatic enzyme systems and usually yield more polar derivatives, referred to as ‘metabolites’, which may leave the body via the urinary and biliary routes or be excreted in animal products such as milk and eggs. Biotransformation does not always imply detoxification because in certain instances metabolites will be produced that are capable of reacting with tissue macromolecules or acquiring toxic properties different to or greater than those of the parent molecule.

In this review, which is focused on domestic animals, the role played by oxidative, reductive, hydrolytic and conjugative biotransformation enzymes in the activation/detoxification of xenobiotics is examined. The relationship between extra-hepatic metabolism and target organ toxicity as well as the action of rumen microflora on feed additives, phytotoxins, and pesticides are then discussed. Some of the most important metabolic-based species-related susceptibilities to different poisons, and the influence of enzyme inducers or inhibitors on xenobiotic toxicity and drug safety are also reviewed.

• 1.

  1. The activity of microsomal drug-metabolizing enzymes—azo reductase, nitroreductase, $\text{p-}\text{hydroxylation}$, N-demethylation, O-demethylation, NADPH cytochrome $\text{c}$ reductase and cytochrome P P-450—in the olive baboon are lower than in other animal species, e.g. mouse, rat, guinea-pig.

• 2.

  2. The level is comparable with the level in man for N-demethylation, azo reductase, O-demethylation and NADPH cytochrome $\text{c}$ reductase.

• 3.

  3. The ratio of the activity of the $\text{p-}\text{hydroxylation}$ as compared with cytochrome P-450 is very similar in baboon and man.

• 4.

  4. Arylsulfatase is localized in the lysosomal fraction and beta-glucuronidase is present more in the lysosomal than in the microsomal fraction.