Other hydroxylase pathways

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Cholesterol is also oxidized to 25-hydroxycholesterol, 27-hydroxycholesterol, and 24- hydroxycholesterol, in liver, lung and brain, respectively. Oxysterols generated in the extrahepatic tissues and organs may be transported to the liver and converted to bile acids. Oxidation of cholesterol is an important mechanism for transport and disposal of biologically active oxysterols, which are potent regulators of cholesterol metabolism (Bjorkhem 2002).

Sterol 25-hydroxylases


In mouse livers, the major cytochrome P450 drug metabolizing enzyme, CYP3A11 is able to catalyze 25-hydroxylation of 5β-cholestan-3α,7α,12α-triol to 5β-cholestan-3α,7α,12α,25- tetrol, which is then converted to cholic acid (Honda et al. 2001). Another enzyme, microsomal cholesterol 25-hydroxylase is a none-heme iron protein that hydroxylates cholesterol to 25-hydroxycholesterol in different tissues (Lund et al. 1998). 25- Hydroxycholesterol is converted to 5β-cholesten-3α,7α,25-triol by CYP7B1 and subsequently converted to bile acids in the liver. However, the 25-hydroxylase pathway may not contribute significantly to bile acid synthesis in humans (Duane et al. 1988).


Sterol 24 hydroxylase

Microsomal sterol 24-hydroxylase (CYP46A1) converts cholesterol to 24(S)- hydroxycholesterol, a cerebrosterol found in the brain and spinal cord (Lund et al. 1999). CYP46A1 is expressed at 100-fold higher levels in the brain than in the liver. Mice lacking the Cyp46a1 gene have normal bile acid synthesis, but markedly reduced cholesterol synthesis and 24-hydroxycholesterol levels in the brain (Lund et al. 2003). This enzyme may play a role in cholesterol turnover in the brain. An oxysterol 7α-hydroxylase (CYP39A1) specific for hydroxylation of 24-hydroxycholesterol has been identified (Li-Hawkins et al. 1994). The 24- hydroxylase pathway contributes very little to overall bile acid synthesis.

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