Cytochrome P450 2D (CYP2D) enzyme dysfunction associated with aging and serotonin deficiency in the brain and liver of female Dark Agouti rats. (January 2022)

• Record Type: Journal Article
• Authors: Haduch, Anna; Danek, Przemysław J.; Kuban, Wojciech; Pukło, Renata; Alenina, Natalia; Gołębiowska, Joanna; Popik, Piotr; Bader, Michael; Daniel, Władysława A.
• Is Part Of: Neurochemistry international. Volume 152(2022)
• Publication Date: 2022-01
• Subjects: CYP2D -- Aging -- TPH2-deficit -- Brain -- Liver -- Females; CYP cytochrome P450 -- TPH2 tryptophan hydroxylase 2 -- TPH2-KO TPH2-knockout; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2021.105223
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: Among the enzymes that support brain metabolism, cytochrome P450 (CYP) enzymes occupy an important place. These enzymes catalyze the biotransformation pathways of neuroactive endogenous substrates (neurosteroids, neurotransmitters) and are necessary for the detoxification processes. The aim of the present study was to assess changes in the CYP2D activity and protein level during the aging process and as a result of serotonin deficiency in the female brain. The CYP2D activity was measured in brain and liver microsomes of Dark Agouti wild type (WT) female rats (mature 15-week-old and senescent 18-month-old rats) and in tryptophan hydroxylase 2 (TPH2)-deficient senescent female rats. The CYP2D activity in mature WT Dark Agouti females was independent of the changing phases of the estrous cycle. In senescent WT females rats, the CYP2D activity and protein level were decreased in the cerebral cortex, hippocampus, cerebellum and liver, but increased in the brain stem. In the other examined structures (frontal cortex, hypothalamus, thalamus, striatum), the enzyme activity did not change. In aging TPH2-deficient females, the CYP2D activity and protein levels were decreased in the frontal cortex, hypothalamus and brain stem (activity only), remaining unchanged in other brain structures and liver, relative to senescent WT females. In summary, the aging process and TPH2 deficit affect the CYP2D activity and protein level in female rats, which may have a negative impact on the compensatory capacity of CYP2D in the synthesis of serotonin and dopamine in cerebral structures involved in cognitive and emotional functions. In the liver, the CYP2D-catalyzed drug metabolism may be diminished in elderly females. The results in female rats are compared with those obtained previously in males. It is concluded that aging and serotonin deficiency exert sex-dependent effects on brain CYP2D, which seem to be less favorable in females concerning CYP2D-mediated neurotransmitter synthesis, but beneficial regarding slower neurosteroid metabolism. Highlights: Aging and cerebral serotonin deficit affect the CYP2D activity in female brain. The enhanced CYP2D activity in the brainstem may increase neurotransmitter synthesis. The decreased CYP2D activity in other brain areas may slow neurosteroid metabolism. Aging, but not cerebral serotonin deficit decrease the CYP2D activity in female liver. Aging and serotonin deficit differently affect CYP2D in females and males.