Potential role of CYP1B1 in the development and treatment of metabolic diseases

Abstract

Cytochrome P450 1B1 (CYP1B1), a member of CYP superfamily, is expressed in liver and extrahepatic tissues carries out the metabolism of numerous xenobiotics, including metabolic activation of polycyclic aromatic hydrocarbons. Surprisingly, CYP1B1 was also shown to be important in regulating endogenous metabolic pathways, including the metabolism of steroid hormones, fatty acids, melatonin, and vitamins. CYP1B1 and nuclear receptors including peroxisome proliferator-activated receptors (PPARs), estrogen receptor (ER), and retinoic acid receptors (RAR) contribute to the maintenance of the homeostasis of these endogenous compounds. Many natural flavonoids and synthetic stilbenes show inhibitory activity toward CYP1B1 expression and function, notably isorhamnetin and 2,4,3',5'-tetramethoxystilbene. Accumulating evidence indicates that modulation of CYP1B1 can decrease adipogenesis and tumorigenesis, and prevent obesity, hypertension, atherosclerosis, and cancer. Therefore, it may be feasible to consider CYP1B1 as a therapeutic target for the treatment of metabolic diseases.

Keywords: CYP1B1; Metabolic diseases; Metabolic pathways; Metabolomics.

Figure 1

Highly potent and selective CYP1B1 inhibitors.

Figure 2

Metabolism of estrogen and estradiol. The Km values for 2- and 4-hydroxylation of estradiol are determined as 0.78 and 0.71 μM (Hayes, et al., 1996). The Vmax values for 2-, 4-, 6α, 6β-, 15α-, and 16α-hydroxylation of estradiol are 0.63, 1.14, 0.15, 0.08, 0.28 and 0.10 nmol/min/nmol P450 (Jansson, et al., 2001).

Figure 3

Metabolism of testosterone. The Vmax values for 6β-, 15α- and 16α-hydroxylation of testosterone are 0.15, 0.02 and 0.09 nmol/min/nmol P450 (Jansson, et al., 2001).

Figure 4

Metabolism of progesterone. The Vmax values for 6β- and 16α-hydroxylation of progesterone are 0.74 and 0.91 nmol/min/nmol P450 (Jansson, et al., 2001).

Figure 5

Metabolism of arachidonic acid. The CYP1B1 and Cyb1b1 Km values for the generation of HETEs and EETS are 29.8 and 500.0 μM, respectively (Choudhary, et al., 2004).

Figure 6

Metabolism of vitamin A. The Km values for retinol and retinal are 18.5 and 8.5 μM (Choudhary, et al., 2004).

Figure 7

Metabolism of melatonin. The Km and Vmax values for 6-hydroxylation of melatonin are determined as 30.9 μM and 5.31 pmol/min/pmol P450 (X. C. Ma, et al., 2005).

Figure 8

Inhibition of CYP1B1 prevents obesity. CYP1B1 deletion diminishes the level of SCD1 expression in the liver, but SCD1 expression level can be normalized in CYP1B1-humanized mice. Studies showed that the deficiency of both CYP1B1 and SCD1 can enhance insulin sensitivity and prevent obesity from HFD challenge. In Cyp1b1-null mice, the expression of lipid synthesis genes are down-regulated, including pyruvate dehydrogenase kinase, isozyme 4 (PDK4), fatty acid synthase (FAS), malic enzyme 1 (ME1), and acetyl-coenzyme A carboxylase beta (ACACB), and the target genes of PPARα involved in the fatty acid oxidation also are decreased, including CD36, ACOT1, ACOT2, CYP4A14, and aldo-keto reductase family 1, member C18 (AKR1C18) (Larsen, et al., 2015). These metabolic changes will cause the decreased generation of phospholipid and tryglyceride. Study in Scd1-null mice have shown the similar changes that the expression of the genes related to lipid synthesis can be decreased such as sterol regulatory element-binding protein 1 (SREBP1), FAS, and, glycerol phosphate acyl-CoA transferase (GPAT). Conversely, the expressions of gene involved in fatty acid oxidation are increased, including CPT1, very long chain acyl-CoA dehydrogenase (VLCAD), and acyl-CoA oxidase (ACO)(Ntambi, et al., 2002). The reduced adipogenesis finally leads to the decrease of weight gain.

Figure 9

Metabolic activation of procarcinogens by CYP1B1 (Adapted from Reference 18). DB[a,l]P is activated by CYP1B1 to the formation of (−)-trans-11,12- dihydrodiol, which is subsequently converted by CYP1B1 to (−)-anti-DB[a,l]PDE. The reaction of (−)-anti-DB[a,l]PDE with 2′-deixyadenosine (Ado) generates (−)-anti-DB[a,l]PDE-DNA adduct that shows the activity of carcinogenesis. Cyp1b1 deletion can reduce the carcinogenesis of DB[a,l]P.

Figure 10

Biochemical links of CYP1B1 between metabolic pathways and metabolic diseases.