Metabolic target-tissue

In humans, most steroids function as hormones, chemical messengers that are secreted by endocrine glands and carried through the bloodstream to target tissues. There are two main classes of steroid hormones the sex hormones, which control maturation, tissue growth, and reproduction, and the adrenocortical hormones, which regulate a variety of metabolic processes. 

Measurement of exposure can be made by determining levels of toxic chemicals in human serum or tissue if the chemicals of concern persist in tissue or if the exposure is recent. For most situations, neither of these conditions is met. As a result, most assessments of exposure depend primarily on chemical measurements in environmental media coupled with semi-quantitative assessments of environmental pathways. However, when measurements in human tissue are possible, valuable exposure information can be obtained, subject to the same limitations cited above for environmental measurement methodology. Interpretation of tissue concentration data is dependent on knowledge of the absorption, excretion, metabolism, and tissue specificity characteristics for the chemical under study. The toxic hazard posed by a particular chemical will depend critically upon the concentration achieved at particular target organ sites. This, in turn, depends upon rates of absorption, transport, and metabolic alteration. Metabolic alterations can involve either partial inactivation of toxic material or conversion to chemicals with increased or differing toxic properties. 

The thyroid hormones are lipophilic and relatively insoluble in the plasma. Therefore, they are transported throughout the circulation bound to plasma proteins such as thyroxine-binding globulin (75%) and albumins (25%). Approximately 99.96% of circulating thyroxine is protein bound. Bound hormone is not available to cause any physiological effects however, it is in equilibrium with the remaining 0.04% that is unbound. This free form of the hormone is able to bind to receptors on target tissues and cause its effects. Thyroid hormone has many metabolic effects in the body ... 

At present a variety of studies with PAH, as well as other chemicals, suggest that metabolic activation in target tissues can occur by one-electron oxidation (6,7). The electrophilic intermediate radical cations generated by thTs mechanism can react directly with various cellular nucleophiles. In this paper, we will discuss chemical, biochemical and biological evidence which indicates that one-electron oxidation plays an important role in the metabolic activation of PAH. 

Although aminoacyl-tRNA synthetases are necessary for protein synthesis in all tissues, their importance in chemical carcinogenesis is difficult to assess. Mutation induction by this pathway has been studied extensively (123), yet metabolic activation in a carcinogen-target tissue has not been demonstrated. The only exception is hepatic prolyl-tRNA synthetase activation of N-hydroxy-Trp-P-2 however, hepatic O-acetylation of this substrate also occurs to an appreciable extent (12). Further investigations involving the use of specific enzyme inhibitors would be helpful in addressing this problem. 

The answer is e. (Hardman, p 21J The fraction of a drug dose absorbed after oral administration is affected by a wide variety of factors that can strongly influence the peak blood levels and the time to peak blood concentration. The Vd and the total body clearance (Vd x first-order fte) also are important in determining the amount of drug that reaches the target tissue. Only the area under the blood concentration-time curve, however, reflects absorption, distribution, metabolism, and excretion factors it is the most reliable and popular method of evaluating bioavailability... 

Metabolic pathway Target tissue Effect of insulin Effect of glucagon... 

Fig. 1.1. General mechanism of action of steroid hormones. Steroid hormones cross through the plasmatic membrane without apparent difficulty favored by gradient. Some, which can be considered prohormones, are metabolized and transformed into more active products. This is the case with testosterone, which becomes dihydrotestosterone (DHT) in the target tissues of androgens, through the 5-alfa-reductase enzyme. The hormone binds to the receptor, a soluble protein of the cellular cytosol that, in the absence of hormone, is found associated with other proteins (hsp90 and others) that maintain the receptor in an inactive state. The hormone-receptor bond causes the other proteins to separate and a homodimer to be formed. The homodimer is the activated form of the receptor since it is capable of recognizing the genes that depend on that steroid hormone as well as of activating its expression, which leads to the synthesis of specific proteins...

Primary hepatocyte cultures have been used in vitro to metabolically activate toxins for evaluation with target tissues. Cocultures of rat embryos with hepatocytes have been used to study the role of metabolism in teratogenesis (Oglesby et al., 1986). Lindahl-Kiessling et al., (1989), in an attempt to bring test conditions closer to in vivo conditions, developed an assay utilizing primary rat hepatocytes and human peripheral lymphocytes to detect metabolism-mediated mutagenesis. 

Target Tissues. The model provided excellent predictions of MMB in both the target tissues of chloroform (liver and kidney) after intraperitoneal administration in mice (rat data was not generated). The model adequately predicted the amount of unchanged material exhaled at infinite time and the total amount metabolized by groups of male and female humans of widely varying age and weight. 

Target Tissues. The Reitz model only applies to the metabolism of chloroform and the induction of cytotoxicity in liver tissue following exposure by inhalation, drinking water, and gavage routes using rat and mouse data. 

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