Induction and metabolism

The placenta is both a transport and a metabolizing organ. Transport is accomplished by simple diffusion, facilitated diffusion, active transport across membranes, and by special processes such as pinocytosis, phagocytosis, specific transport molecules, and channels in the barrier . The placenta also contains a full complement of mixed function oxidases located in the microsomal and mitochondrial subcellular fractions capable of induction and metabolism of endogenous and exogenous chemicals. 

There is an important class of chemicals for which assessment of exposure times is even more complicated. Indirect-acting chemicals are not themselves active and must be metabolized to more active intermediates. Some cultured cells are better able to metabolize these chemicals than others e.g., benzo[a]pyrene induces more SCEs in cultured lymphocytes than in cultured CHO cells, provided the duration of exposure is at least 24 hr. Craig-Holmes and Shaw(23) suggested that in lymphocytes, benzo [a] pyrene induces the enzyme aryl hydrocarbon hydroxylase necessary for its own metabolism and that this induction and metabolism are brought about only if the cells are exposed to the chemical for at least 24 hr. If this is also true for SCE induction by other indirect-acting chemicals in cell types capable of metabolism, a long duration of exposure is necessary unless some other form of enzyme induction is used. 

Emphasis is given to the critical role of metabolism, both detoxication and activation, in determining toxicity. The principal enzymes involved are described, including monooxygenases, esterases, epoxide hydrolases, glutathione-5 -transferases, and glucuronyl transferases. Attention is given to the influence of enzyme induction and enzyme inhibition on toxicity. 

Other factors such as drug interactions that result in inhibition or induction of both CYP3A4 and PGP may influence the bioavailability and metabolism of their... 

Hammerstiom K, Dethier MN, Duggins DO (1998) Rapid phlorotannin induction and relaxation in five Washington kelps. Mar Ecol Prog Ser 165 293-305 Haslam E (1985) Metabolites and metabolism. Clarendon, Oxford... 

Chadwick RW, Chadwick CJ, Freal JJ, et al. 1977. Comparative enzymes induction and lindane metabolism in rats pre-treated with various organochlorine pesticides. Xenobiotica 7(4) 235-246. 

The third and final control step is mediated by PK. This enzyme, like HK, exists as a number of isoenzymes in different tissues and, like the PFK reaction, is controlled by both the concentration of metabolites and covalent effects. Furthermore, PK also illustrates two other means of metabolic control, namely enzyme induction and feedforward, regulation. 

Electron paramagnetic resonance (EPR) examination of hepatic microsomes from differently pretreated animals has lead to the conclusion that MC pretreatment leads to the formation of cytochrome P-1+50 (P-1+1+8) with high spin iron (6, 1+6). Chevion et al. (28) failed to demonstrate the presence of high spin cytochrome P-1+50 in a teleost fish even after induction with MC. The work of Chevion et al. (28 ) indicates further that the fish cytochrome P-1+50, which is inducible with PAH s and metabolizes readily PAH s, is not identical with the mammalian cytochrome P-1+1+8. 

Isolated capillaries have been used for a long time to study transport and metabolic function of the blood-brain barrier [61, 72, 75, 76, 78, 87-91], In contrast to monolayer cell cultures, which are susceptible to induction or inhibition of carrier protein expression, experiments with freshly isolated capillaries directly reflect the situation at the luminal side of brain capillaries. 

Many reported biotransformations are initially only demonstrated on a very small scale, the substrates or products may be subject to competing reactions if other enzymes are present (this can be a serious issue in whole-cell biocatalysis), or the desired enzyme is insufficiently active or produced in low levels. For many biotransformations a little care and attention is needed in the growth of the microbe to achieve the desired results. Production of a specific enzyme from a microbe can often be increased by growing the cells in the presence of a very small concentration (typically micromolar) of an inducer. The inducer could be a natural enzyme substrate, a substrate mimic or a molecule which is in some way associated with a substrate s availability or role in metabolism. This process is called induction and represents a genetic switch which cells use to respond... 

When data are available to enable comparison of the plasma concentration time profile after single administration with that after repeated administration, this would enable determination of whether the substance has time dependent kinetics (due to induction of metabolism, inhibition of metabolism, and/or accumulation and saturation of processes involved in distribution, metabohsm, and excretion). 

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