Thyroid hormone 26-hydroxylation, effect

Metabolites of PCBs also exert biological effects. The Ah-receptor mediated responses, however, are probably caused by the parent compounds only. The effects of hydroxylated PCBs include inhibition of cytochrome P450-dependent enzyme activities and competitive interference with thyroid hormone and vitamin A metabolism.89,90 Methylsulfonyl-PCBs have been shown to inhibit aryl hydrocarbon hydroxylase activity91 and to elicit phenobarbital-type toxicity and may in fact be responsible for the observed effect presumed to be caused by the parent compound.92... 

Schuur AG, Bergman A, Brouwer A, et al. 1999. Effects of pentachlorophenol and hydroxylated polychlorinated biphenyls on thyroid hormone conjugation in a rat and a human hepatoma cell line. Toxicol in Vitro 13 417-425. 

The properties of the ihicrosomal 26-hydroxylase seem to differ from those of the other microsomal side-chain hydroxylations. Treatment with phenobarbital had little or no influence on 26-hydroxylation of 5yS-cholestane-3a,7a,12a-triol but stimulated the other hydroxylations up to 8-fold [126]. Thyroid hormone stimulated the microsomal 26-hydroxylase, which might be of importance for the regulation of the ratio between cholic and chenodeoxycholic acid in the rat (cf. below). Biliary obstruction inhibited [127] whereas biliary drainage and starvation have little or no effect [126]. 

Early in vitro studies showed that mitochondria from livers of hyperthyroid rats did not oxidize cholesterol-26- C to C02 at a faster rate than similar preparations from normal animals (12). A more recent study (13) led to the conclusion that the effects of thyroid hormones on bile acid metabolism must take place at a biosynthetic step preceding side-chain oxidation, perhaps involving hydroxylation of the steroid nucleus. However, it must be realized that the normal substrate for side-chain oxidation leading to the formation of cholic acid from cholesterol is not cholesterol itself but presumably 3a,7afl2a-trihydroxy-5/5-cholestane (14,15), and the substrate for the side-chain oxidation leading to chenodeoxycholate is, presumably, 3a,7a-dihydroxy-5/5-cholestane (16). Thus results of in vitro experiments in which cholesterol is employed as the substrate must be interpreted with caution, since mitochondria do not have the enzyme system required for formation of the triol and diol from cholesterol. 

More recently, it has been shown that the 12a-hydroxylation of 7a-hydroxycholest-4-en-3-one (an intermediate in cholic acid synthesis) is increased in homogenates from hypothyroid rats and decreased in homogenates from hyperthyroid rats (18). Thyroid hormone, therefore, may exhibit a specific inhibitory effect on the hydroxylation of 7a-hydroxycholest-4-en-3-one. This could explain, in part, the increased chenodeoxycholate... 

Sarafian T, Verity MA (1986) Mechanism of apparent transcription inhibition by methylmercury in cerebellar neurons. J Neurochem 47 625-631 Sin YM, Teh WF (1992) Effect of long-term uptake of mercuric sulphide on thyroid hormones and glutathione in mice. Bull Environ Contam Toxicol 49 847-854 Suda I, Hirayama K (1992) Degradation of methyl and ethyl mercury into inorganic mercury by hydroxyl radical produced from rat liver microsomes. Arch Toxicol 66 398-402... 

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