Is there a possibility that P-glycoprotein reduces reproductive toxicity in males but breast cancer resistance protein does not?

Abstract

In traditional understanding, P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are regarded as efflux transporters that can decrease the concentration of their substrates in the testis, thereby reducing reproductive toxicity in males (RTM) and protecting spermatogenesis. However, there is currently no direct pharmacological evidence demonstrating that P-gp and BCRP can reduce the occurrence of drug-induced RTM. In this study, we chose small molecule targeted anti-tumor agents as model drugs and systematically retrieved and collected information on the transporters and RTM for these drugs, followed by correlation analysis. The results showed a lower incidence of RTM for P-gp substrate drugs, which aligns with previous knowledge. Surprisingly, BCRP substrate drugs exhibited higher rates of RTM in various dimensions, contradicting previous notions. This discrepancy may be attributed to the differential distribution and transport directions of P-gp and BCRP on the blood-testis barrier (BTB). For the first time, this study may provide clues that BCRP may facilitate the passage of exogenous compounds across the BTB, increasing the occurrence of RTM, rather than protecting spermatogenesis as traditionally believed. Furthermore, this study provides the first direct verification of the role of P-gp in reducing RTM and protecting spermatogenesis.

FIGURE 1

The relationship between RTM and transporter information of drugs (*p < 0.05).

FIGURE 2

The relationship between RTM and transporting ability of P‐gp and BCRP for dual‐substrate (*p < 0.05).

FIGURE 3

Exposure ratios in rats for RTM drugs. (a) Drugs transported by P‐gp or/and BCRP and none. (b) Drugs transported by BCRP and non‐BCRP.

FIGURE 4

The structure of the Blood–Testis Barrier.

FIGURE 5

The single‐cell RNA sequencing of ABCG2 in testis. SPG1‐Spermatogonia, SPG2‐Spermatogonia in the differentiation, SPG3‐differentiated spermatogonia, L‐Spermatocyte in the thin line stage, Z‐Spermatocyte in the even‐line stage, P‐Spermatocyte in the thick line stage, D‐Spermatocyte in the two‐line stage, SEC‐Secondary Spermatocyte, S‐Spermatozoa, ST‐Sertoli cell.