Biotransformation

Principles and Practices of Toxicology in Public Health written by Ira S. Richards indicates the importance of understanding biotransformation. This process is the sum of all chemical processes of the body that modify endogenous or exogenous chemicals. This heavily applies to the concept of toxicokinetics which is the process at what rate a chemical will enter the body and what will happen when it is applied. Areas of focus within toxicokinetics besides biotransformation include: absorption, distribution, storage, and elimination.

Biotransformation Factors

Biotransformation is strongly affected by factors pertaining age, sex, existing disease, genetic variability (toxicogenetics), enzyme induction, and nutritional status. The ability to metabolize a toxin can vary greatly with age. For the developing fetus and very young, limited biotransformation capability is noted primarily due to the lack of important enzymes. With this being said, the elderly can also have difficulties with this process due to loss of function with aging. Differences in hormones also account for gender-specific variability of some toxicants. Specific vitamins, minerals, and protein deficiencies can decrease the body's ability to synthesize the essential enzymes needed for biotransformation.

Enzymes

Enzymes generally reach their optimal capacity for this process by the time adulthood is reached. Enzyme fluctuations are at their lowest in early adulthood, which corresponds with the most efficient time for metabolism. These are considered biological catalysts and high-molecular-weight proteins they allow for biotransformation reactions to occur at rates that are consistent with life. "Lock and key" arrangement is often times referred to the process in which enzymes provide the molecular surface for a chemical reaction to proceed for substrates with the correct molecular architecture to fit onto the anchoring reaction sites. Without this, biotransformation uf the substrate may not proceed and the degree of enzyme specificity for substrates determine the extent of involvement with different chemicals. This degree of specificity may be absolute and catalyze only one specific reaction, may be less restrictive and catalyze reactions of structurally similar chemicals such as those with a particular type of chemical bond or functional group.

Biotransformation Phase 1

The University of Idaho indicates that this phase is commonly known for its involvement in functional group modification. In Phase 1 of biotransformation, oxidation enzyme reactions are considered the most important. This process adds an oxygen, removes a hydrogen, and increases valence. Reduction reactions also occur in this phase and are considered to be of less importance compared to oxidation. They remove an oxygen, add a hydrogen, and decrease valence. Hydrolysis reactions also occur in this phase which adds a water to the chemical component. 

Principles and Practices of Toxicology in Public Health continues to state that these reactions can be either microsomal or nonmicrosomal and are considered to be very polar (water-loving). Enzyme induction occurs, which is the process in which results in an increased ability to metabolize toxicants. Because Phase 1 is polar and causes the metabolite to be more hydrophillic (water-loving) in nature, it requires additional biotransformation to further increase hydrophillicity that is sufficient enough to permit significant elimination from the body. This is where Phase 2 comes in. 

Biotransformation Phase 2

Metabolites that have undergone Phase 1 of biotransformation produce an intermediate metabolite that now contains a "polar handle", such as a carboxyl, amino acid, or hydroxyl functional group. Conjugation reactions occur in this phase, indicating the combination of two or more chemical compounds. Muhammad Bilal Mirza indicates that Phase 2 is when the parent drug participates in the formation of covalent linkage between the parent compound functional group and either a glucuronic acid, sulfate, glutathione, amino acid, or an acetate compound, Conjugates are considered to be high in molecular weight, generally inactive, and rapidly excreted in urine. The primary organ that is affected by Phase 1 and Phase 2 of biotransformation is the liver. Other metabolizing organs that are affected include: gastrointestinal tract lungs, kidney, and the skin.