Benzo -pyrene metabolic pathways

No studies were located regarding the metabolic pathway of fuel oils in humans. In one animal study, fuel oil no. 2 applied to the skin of rats induced cutaneous aryl hydrocarbon hydroxylase activity in rat skin microsomal preparations by causing a three-fold induction of benzo(a)pyrene (BaP) 3-hydroxylase activity (Rahimtula et al. 1982). In addition, BaP 3-hydroxylase activity was selectively inhibited by -naphthoflavone, but not by metyrapone, suggesting that cytochrome P-448 enzymes are induced and may participate in the metabolism of this fuel oil (Rahimtula et al. 1982). 

Figure 12.12 Benzo[a]pyrene metabolism to the ultimate carcinogenic species. Heavy arrows indicate major metabolic pathways, represents ultimate carcinogenic species. (Adapted from A. H. Conney, Cancer Res. 42 4875, 1982.)...

Epoxidation is thought to be the major pathway for benzo[a]pyrene metabolism pertinent to macromolecular interaction. The metabolic attack consists of the cytochrome P-450/P-448-dependent MFO system converting the benzo[a]pyrene molecule into an epoxide the epoxide is acted upon by epoxide hydrolase to form a dihydrodiol, and a second cytochrome MFO reaction gives rise to the ultimate mutagenic/carcinogenicform, benzo[a]pyrene 7, 8-diol-9,... 

It is clear that the effects of induction or inhibition of the metabolism will be complex, due to the large number of possible metabolic pathways through which benzo [ajpyrene may be metabolized. For instance, the microsomal enzyme inducer 5,6-benzoflavone inhibits the carcinogenicity of benzo [a] pyrene to mouse lung and skin, whereas inhibitors such as SKF 525A may increase the tumour production from certain polycyclic hydrocarbons. 

Figure 1 Selected metabolic pathways of benzo(a)pyrene. Glue, glucuronidase Suit, sulfatase R, glucuronate or sulfate MFO, mixed function oxidases GST, glutathione-S-transferase EH, epoxide hydrolase.

Two interferon-Y-controUed metabolic pathways accounting for some of the cytostatic effects of interferon-y in rat pleural mesothelial cells transformed in vitro with benzo[a] pyrene or chrysotile asbestos were not efficient in human mesothelioma cells, and suggested that cytokine-induced growth inhibition is mediated by a different pathway in human mesothelioma cell lines (Phan-Bitch etal. 1997). 

The stereoselective metabolism of benzo(a)pyrene to an ultimate carcinogen has been well documented, and the metabolic pathway follows the sequence BP BP-7,8-oxide BP-7,8-dihydrodiol BP-7,8-diol-9,10-epoxide (Figure 4.8). The enantioselective toxicities of BP-7,8-dihy-drodiol and BP-7,8-diol-9,10-epoxide have already been discussed, but in order to study the biological effects of (+)- and (—)-benzo(a)pyrene 4,5-oxide, a synthesis of these molecules has been developed based on... 

Although the PAHs are similar, they have structural differences that are the basis for differences in metabolism and relative carcinogenicity. The metabolism of the more carcinogenic, alternant (equally distributed electron density) PAHs, such as benzo(a)pyrene, benzo(a)anthracene, and dibenz(a,h)anthracene, seems to differ in some ways from that of nonalternant (imeven electron density distribution) PAHs, such as fluoranthene, benzo(b)fluoranthene, benzo(k)fluoranthene, benzo(j)fluoranthene, and indeno(l,2,3-cd)pyrene [31]. As can be seen, most of the studies on the metabolic pathways of PAHs have been done on rodent, therefore little is known on the metabolism of these compounds in nonrodent species. Due to specie differences there may be some slight differences in the enzymes that activate PAHs and in the formation of DNA adducts. 

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