Toxicity Effect Of Cyclophosphamide On Bone Marrow Of Mice With Modulation Of The Liver P450

Cyclophosphamide (CP) is one of the most widely used anticancer drugs. CP may bring about some severe toxicities such as myelosuppression, hemorrhagic cystitis, hair lose and gonad damage. Of all the toxicities, bone marrow damage is the most important one. CP is an anticancer alkylating agent that requires bioactivation by hepatic cytochromes P450 (CYP, P450) with two alternative pathways. One is activiting pathway in which CP 4-hydroxylation is turned to 4-hydroxylation-CP (4-OH-CP), and then is decomposed to phosphsramide mustard, a DNA-alkylating cytotoxic metabolite. CP 4-hydroxylation is mainly catalyzed by the liver P450 subsets P4502B and P4502C. The other pathway is inactivated involving N-dechloroethylation and decomposition to dechloroethyl-CP and chloroacetaldehyde (CA), a P4503A catalyzed deactivation reaction. Phenobarbital (PB) and dexamethasone (DEX) are P450 inducers while troleandomycin (TAO) can inhibit P4503A activity. The paper studied effect of CP on bone marrow toxicity in mice by modulating liver P450 with PB, DEX and TAO to observe whether the marrow toxicity of CP could be reduced by the P450 modulators.(1) Mouse liver microsomes were prepared using polyethylene glycol and the total content of P450 and P4503A activity were measured. The total content of P450 in PB and DEX treated mice increased by 1.82 and 3.32 times of the control. In contrast, total content of P450 of CPdecreased 46.78%. Compared with the control, the rate of P4503A-catalyzed N-demetylation of erthromycin increased by 8.30 and 4.82 times in DEX and PB treated mice.(2) mice treated with PB, DEX or TAO and then 40mg/kg CP i.p for 4 days were sacrificed at 7th day after the treatment. Then body weight change, bone marrow cell (BMC) count, peripheral blood cell counts, the mumber colony-forming units-granulocyte/macrophage (CFU-GM) and pathologic histology of the bone marrow were measured. Compared with the CP treated mice, DNA content and erythroid cell increased significantly in PB treated mice; body weight change, Granulocytic cell/erythroid cell, and CFU-GM increased significantly in DEX treated mice; WBC, BMC and erythroid cell increased significantly in TAO treated mice.In summary, TAO could reduce the CP marrow toxicity and improve system toxicity of mice. DEX could improve system toxicity and reduce toxicity on granuloclytic cell of mice induced by CP. These effects were modulated through the reduction of PM production and enhancement of the 4-hydrlxilation pathway. The results provided experimental basic for future studies on reduce toxicity of the anticancer drugs by way of modulation of the P450 activity.