BIOTRANSFORMATION

Biotransformation

Biotransformation

Introduction

Biotransformation is the process whereby a substance is changed from one chemical to another (transformed) by a chemical reaction within the body. Metabolism or metabolic transformations are terms frequently used for the biotransformation process. However, metabolism is sometimes not specific for the transformation process but may include other phases of toxicokinetics. (Martins et al 2008)

Factors effecting biotransformations and drug response

The relative effectiveness of biotransformation depends on several factors, including species, age, gender, genetic variability, nutrition, disease, exposure to other chemicals that can inhibit or induce enzymes, and dose levels. Differences in species capability to biotransform specific chemicals are well known. Such differences are normally the basis for selective toxicity, used to develop chemicals effective as pesticides but relatively safe in humans. For example, malathion in mammals is biotransformed by hydrolysis to relatively safe metabolites, but in insects, it is oxidized to malaoxon, which is lethal to insects. (Meyer, Panke, 2008)

Safety testing of pharmaceuticals, environmental and occupational substances is conducted with laboratory animals. Often, differences between animal and human biotransformation are not known at the time of initial laboratory testing since information is lacking in humans. Humans have a higher capacity for glutamine conjugation than laboratory rodents. Otherwise, the types of enzymes and biotransforming reactions are basically comparable. For this reason, determination of biotransformation of drugs and other chemicals using laboratory animals is an accepted procedure in safety testing. (Diaz, 2008)

Age may affect the efficiency of biotransformation. In general, human fetuses and neonates (newborns) have limited abilities for xenobiotic biotransformations. This is due to inherent deficiencies in many, but not all, of the enzymes responsible for catalyzing Phase I and Phase II biotransformations. While the capacity for biotransformation fluctuates with age in adolescents, by early adulthood the enzyme activities have essentially stabilized. Biotransformation capability is also decreased in the aged. Gender may influence the efficiency of biotransformation for specific xenobiotics. This is usually limited to hormone-related differences in the oxidizing cytochrome P-450 enzymes.

Genetic variability in biotransforming capability accounts for most of the large variation among humans. The Phase II acetylation reaction in particular is influenced by genetic differences in humans. Some persons are rapid and some are slow acetylators. The most serious drug-related toxicity occurs in the slow acetylators, often referred to as "slow metabolizers". With slow acetylators, acetylation is so slow that blood or tissue levels of certain drugs (or Phase I metabolites) exceeds their toxic threshold. (Martins ...