Drug metabolism benzo pyrene

Each plant tissue tends to have an obviously distinctive profile of flavonoids. The flavonoid content can reach about 0.5% in pollen, 10% in propolis, and about 6 mg/kg in honey. Havonoid aglycones appear to be present only in propolis and honey, while pollen contains flavanols in herosidic forms. The flavonoids in honey and propolis have been identified as flavanones and flavanones/flavanols (Campos et ah, 1990). The antimi-crobially active flavanone pinocembrine was foimd to be a major flavonoid in honey (Bogdanov, 1989). Amiot et ah (1989) studied two blossom and two honeydew Swiss honey samples and foimd that pinocembrine was the main flavonoid. Pinocembrine concentration varied between 2 and 3 mg/kg (Bogdanov, 1989). Berahia et ah (1993) analyzed sunflower honey samples and detected six flavone/flavols, four flavanone/ flavols, and pinocembrin, of which pinocembrin is the main flavonoid. The flavonoids in sunflower honey and propolis were characterized and assessed for their effects on hepatic drug-metabolizing enzymes and benzo [fl]pyrene-DNA adduct formation (Sabatier et ah, 1992 Siess et ah, 1996). 

The next process we consider is drug metabolism. The study of oxidation reactions in compounds such as benzo (a) pyrene has emphasized the P450-dependent oxidation systems of the liver toxicologists have virtually Ignored other potentially important oxidizing systems. Future research may find drug-oxidation systems which are not P450-linked, and even other membrane-bound and non-membrane-bound oxidative and reductive systems in whole animal cells. 

Environmental chemicals and pollutants are also capable of inducing P450 enzymes. As previously noted, exposure to benzo[a]pyrene and other polycyclic aromatic hydrocarbons, which are present in tobacco smoke, charcoal-broiled meat, and other organic pyrolysis products, is known to induce CYP1A enzymes and to alter the rates of drug metabolism. Other environmental chemicals known to induce specific P450s include the polychlorinated biphenyls (PCBs), which were once used widely in industry as insulating materials and plasticizers, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, TCDD), a trace byproduct of the chemical synthesis of the defoliant 2,4,5-T (see Chapter 56). 

Miller, K. P. Ramos, K. S. (2001). Impact of cellular metabolism on the biological effects of benzo[u]pyrene and related hydrocarbons. Drug Metabolism Reviews, 33, 1-35. 

SELECTIVE ENZYME INDUCTION BY BENZO [A] PYRENE EVIDENCE FOR MULTIPLE DRUG-METABOLIZING ENZYMES... 

Gupta PH, Mehta S, Mehta SK. 1989. Effects of dietary benzo(a)pyrene on intestinal phase I and phase II drug metabolizing systems in normal and vitamin A-deficient rats. Biochem Int 19(4) 709-722. 

Soyka LF. 1980. Hepatic drug metabolizing enzyme activity and tumorigenesis in mice following perinatal exposure to benzo(a)pyrene. Pediatr Pharmacol 1 85-96. 

Figure 9.1. Sex-differences in rat hepatic microsomal drug metabolism. Data shown are based on enzyme assays in rat liver microsomes using the three indicated xenobiotic substrates ethylmorphine (EM), benzo[o] pyrene (BP), and hexobarbital (HB). Ethylmorphine A -demethylase and benzo[a]pyrene hydroxylase activities are expressed as nmol product formed per minute per mg microsomal protein, whereas hexobarbital hydroxylase activity is expressed as nmol product formed per 30 min per g liver. Also shown is hepatic microsomal total cytochrome P450 content, which is expressed as nmol per mg microsomal protein (values multiplied by 10). The data are shown as mean SD for 4 or 5 rats, except for ethylmorphine W-demethylase and total P450 which are based on a pool of 6 livers.

The MFO system is also known as the aryl hydrocarbon hydroxylase (AHH) or drug-metabolizing system in mammals. In fish, as in mammals, most MFO activity is localized in the liver (2.404 /imoles of B[a]P hydroxylase = AHH) and in minor amounts in kidney (0.026) and heart (0.006) (Pederson etaL, 1974). Many studies have shown the presence of various oxygenases in fish (Bend etal, 1977 Stegeman, 1978). AHH is present in many marine fish species from different habitats and life stories (Payne, 1977). Several fish species including rainbow trout can hydroxylate benzo[a]pyrene and naphthalene. Quantitative data on AHH activity based on B[a]P hydroxylase activity, benzphetamine demethylase activity, 7-ethoxycoumarin deethylase activity, and cytochrome P-450 content in vertebrates, crustaceans, and bivalves are available in the literature (Vandermeulen and Penrose, 1978 Philpot etaL, 1976). Specific enzyme activities derived from single substrate measurements are limited in their application to complex mixtures of petroleum hydrocarbons (Malins, 1977a, b). MFO absence or activity could determine hydrocarbon retention in... 

In contrast, the primary role of microsomal EH appears to be in detoxifying the metabolically produced epoxides of drugs, e.g., carbamazepine epoxide, the arene oxide of diphenylhydantoin, and the epoxides of environmental contaminants like the polycyclic aromatic hydrocarbons, e.g., benzo[a]pyrene. 

K. P. Miller, K. S. Ramos, Impact of Cellular Metabolism on the Biological Effects of Benzo[a]pyrene and Related Hydrocarbons , Drug Metab. Rev. 2001, 33, 1 - 35. 

Cutaneous biotransformation is mostly associated with the stratum basale layer where there can be phase I and phase II metabolism. However, the skin is not very efficient, compared to the liver. The epidermal layer accounts for the major portion of biochemical transformations in skin, although the total skin activity is low (2-6% that of the liver). Where activity is based on epidermis alone, that layer is as active as the liver or, in the case of certain toxicants, several times more active. For some chemicals, metabolism can influence absorption, and transdermal delivery systems of drugs utilize this activity. For example prodrug such as lipid esters are applied topically, and cutaneous esterases liberate the free drug. These basal cells and extracellular esterases have been shown to be involved in detoxification of several pesticides and bioactivation of carcinogens such as benzo(a)pyrene. For rapidly penetrating substances, metabolism by the skin is not presently considered to be of major significance, but skin may have an important first-pass metabolic function, especially for compounds that are absorbed slowly. 

In essence, first-pass elimination kinetics means that, if a chemical administered by any route is metabolized before it reaches a target tissue, it will cause no response in that tissue. Hence, the forms of P-450 induced in the intestine and liver metabolize most of the benzo [a] pyrene given orally to the Ah-responsive mouse the amount of parent drug or its metabolites reaching the bone marrow is therefore greatly decreased. 

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